Synthesis of novel derivatives of 2-(azolylimino)thiazoline

Article abstract of DOI:10.1007/s11172-005-0116-8

Successive alkylation of 5-(3-phenylthioureido)-3H-imidazole-4-carboxamides with alkyl halides and chloroacetone gave (N-oxopropylimidazolyl)isothioureas, which were easily converted into derivatives of purine and imidazopyrazinone. In the case of ethyl 5

Full text of DOI:10.1007/s11172-005-0116-8

Russian Chemical Bulletin, International Edition, Vol. 53, No. 10, pp. 2293—2302, October, 2004
2293
✾
Synthesis of novel derivatives of 2ꢀ(azolylimino)thiazoline
O. S. Eltsov,aꢀ V. S. Mokrushin,a and A. V. Tkachevb
aUral State Technical University,
19 ul. Mira, 620002 Ekaterinburg, Russian Federation.
Fax: +7 (343 2) 75 4135. Eꢀmail: eltsov@htf.ustu.ru
bN. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry,
Siberian Division of the Russian Academy of Sciences,
9 prosp. Akad. Lavrent´eva, 630090 Novosibirsk, Russian Federation.
Fax: +7 (383 2) 34 4752. Eꢀmail: atkachev@nioch.nsc.ru
Successive alkylation of 5ꢀ(3ꢀphenylthioureido)ꢀ3Hꢀimidazoleꢀ4ꢀcarboxamides with alkyl
halides and chloroacetone gave (Nꢀoxopropylimidazolyl)isothioureas, which were easily conꢀ
verted into derivatives of purine and imidazopyrazinone. In the case of ethyl 5ꢀ(3ꢀphenylꢀ
thioureido)ꢀ3Hꢀimidazoleꢀ4ꢀcarboxylate, primary alkylation occurs at the N atom of the imidꢀ
azole ring. Reactions of 5ꢀ(3ꢀphenylthioureido)ꢀ3Hꢀimidazoleꢀ4ꢀcarboxamides with haloꢀ
ketones afforded a number of 4ꢀhydroxyꢀ2ꢀimidazolyliminothiazolidines and 2ꢀimidazolylꢀ
4
iminoꢀ∆ ꢀthiazolines.
4
Key words: haloketone, alkylation, 2ꢀimidazolyliminoꢀ∆ ꢀthiazolines, imidazo[5,1ꢀc]pyrꢀ
azinꢀ7ꢀones, imidazolylthiourea, purine derivatives, alkyl halides, (Nꢀalkylimidazolyl)isoꢀ
thioureas.
At present, a successful search for new biologically
In contrast to imidazolylthioureas 2a—c, thioureide
active substances among 2ꢀazolylthiazolines is being conꢀ
ducted.1,2 The goal of this study was to obtain imidazole
analogs of antipyriliminothiazolines, which exhibit antiꢀ
inflammatory activity.2
2d reacts with haloalkanes 6a,b and chloroacetone to give,
as noted earlier,4 Nꢀalkylimidazolylthioureas 7a—c. The
reactions of compounds 7a—c with haloketones 3a—d
afforded the target products 5m—x; however, in contrast
to compounds 2a—c, intermediate 2ꢀ(Nꢀalkylimidazolylꢀ
imino)ꢀ4ꢀhydroxythiazolidines of the type 4 could not be
isolated.
One of the most rational ways of synthesizing thiazole
compounds is condensation of thioureido derivatives with
haloketones.3 We found (Scheme 1) that imidazolylꢀ
thioureas 2a—c obtained by reactions of 5ꢀaminoimidꢀ
azoles 1a—d with phenyl isothiocyanate react with haloꢀ
ketones 3a—d to give stable 4ꢀhydroxyꢀ2ꢀimidazolylꢀ
iminothiazolidines 4a—l. Their structures were confirmed
Analysis of the 1H NMR spectra of compounds 5a—x
and the 13C NMR spectra of compounds 5b,m—o showed
that their heterocyclic systems are identical. For instance,
the 13C chemical shifts of the carbon atoms of the
thiazoline fragment are very close for compounds 5b and
5n (spaced at 0.5 to 1.9 ppm). The 1H and 13C signals for
the imidazolyliminothiazoline 5n were assigned by using
1
by data from H NMR spectroscopy and mass spectromꢀ
1
etry. The H NMR spectra show resonance signals at
δ 3.7—3.4 (AB system) for the nonequivalent CH2 proꢀ
tons of the thiazolidine ring and no signals for the NH
protons. The mass spectra of these compounds contain
molecular ion peaks (Table 1). It should be noted that in
the presence of CD3CO2D, the 1H NMR spectra of comꢀ
pounds 4a—l show singlets for the CH protons of the
thiazoline ring, the integrated intensity of the signals for
the CH2 protons of the thiazolidine ring being reduced.
The discovered process was confirmed preparatively: when
heated in acetic acid at 70 °C, compounds 4a—l rapidly
lose a water molecule to form 2ꢀimidazolyliminoꢀ∆4ꢀ
1
2D H—1H and 13C—1H COSY NMR spectroscopy for
direct (J = 135, 165, and 195 Hz) and longꢀrange
(J = 10 Hz) spinꢀspin coupling constants. The tentative
structure of compound 5n was fully confirmed by Xꢀray
diffraction data.4 The proof of the structures of products
5a—x allows a conclusion about similar structures of inꢀ
termediates 4a—l.
Unlike compound 2d, thioureas 2a—c react with alkyl
halides to give Sꢀalkylation products 8a—f. In particular,
their 1H NMR spectra show the signals for the protons of
the alkyl residue (CH2S) at δ 2.96—3.16. Subsequent reꢀ
actions of isothioureas 8a—f with chloroacetone could be
expected to yield both (Nꢀalkylimidazolyl)isothioureas
through the involvement of an N atom of the imidazole
1
thiazolines 5a—l. In their H NMR spectra, a signal for
the proton of the thiazole ring appears at δ 6.3—6.5; the
molecular ion peaks in the mass spectra correspond to the
peaks [M – 18]+ in the spectra of intermediates 4a—l.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 2196—2204, October, 2004.
1066ꢀ5285/04/5310ꢀ2293 © 2004 Springer Science+Business Media, Inc.

2294
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 10, October, 2004
Eltsov et al.
Scheme 1
1, 2: R1 = NH2 (a), NHMe (b), NHC6H4ꢀMeꢀp (c), OEt (d)
4, 5
R1
R2
5
R2
R3
a
b
c
d
e
f
g
h
i
NH2
NHMe
NHC6H4Meꢀp
NH2
NHMe
NHC6H4Meꢀp
NH2
NHMe
NHC6H4Meꢀp
NH2
NHMe
Me
Me
Me
Ph
Ph
Ph
C6H4Meꢀp
C6H4Meꢀp
C6H4Meꢀp
C6H4Clꢀp
C6H4Clꢀp
C6H4Clꢀp
m
n
o
p
q
r
s
t
u
v
Me
Me
Me
Ph
Ph
Ph
C6H4Meꢀp
C6H4Meꢀp
C6H4Meꢀp
C6H4Clꢀp
C6H4Clꢀp
C6H4Clꢀp
Et
Pr
3: R2 = Me (a), Ph (b), C6H4ꢀMeꢀp (c), C6H4ꢀClꢀp (d);
Hal = Cl (a), Br (b—d)
CH2COMe
Et
Pr
CH2COMe
Et
Pr
CH2COMe
Et
Pr
4a—l, 5a—l: R3 = H; 5m—x: R1 = OEt
6: R3 = Et, Hal = I (a); Pr, Br (b);
7: R3 = Et (a), Pr (b), CH2COMe (c)
j
k
l
w
x
NHC6H4Meꢀp
CH2COMe
ring and fused bicyclic compounds (imidazopyrazines or
imidazotriazepines) as the result of intramolecular cyꢀ
clization. The H NMR spectra of the compounds obꢀ
tained contain two signals at δ 11.6—11.8 for the NH
fragments and a singlet at δ 5.1 for the CH2 group,
which corresponds to the structure of Nꢀsubstituted
1
Table 1. Characteristics of the compounds obtained
Comꢀ Yield
pound (%)
M.p.
/°C
Found
Calculated
Molecular
formula
(%)
C
H
N
S
Cl
—
2a
2b
2c
2d
4а
75
82
87
72
61
>300
>300
50.80
50.57
52.58
52.36
61.22
61.54
53.55
53.79
52.90
52.98
4.04
4.21
4.90
4.73
4.99
4.84
4.61
4.83
4.92
4.76
27.00
26.82
25.54
25.45
19.78
19.94
19.50
19.31
22.22
22.07
12.20
12.27
11.81
11.64
9.00
C11H11N5OS
C12H13N5OS
C18H17N5OS
C13H14N4O2S
C14H15N5O2S
—
—
—
—
>300
9.12
192—193
144—145
10.95
11.03
9.91
10.10
(to be continued)

Synthesis of novel 2ꢀ(azolylimino)thiazolines
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 10, October, 2004
2295
Table 1 (continued)
Comꢀ Yield
pound (%)
M.p.
/°C
Found
Calculated
Molecular
formula
(%)
C
H
N
S
Cl
—
4b
4c
4d
4e
4f
82
83
70
95
98
84
93
90
75
96
93
69
71
78
79
88
80
80
74
85
71
74
68
42
41
40
256—258
263—264
141—143
284—285
>300
54.19
54.37
62.05
61.90
60.29
60.14
61.21
61.05
66.70
66.51
61.21
61.05
61.78
61.90
67.24
67.06
55.31
55.14
55.98
56.14
61.78
61.90
56.27
56.17
57.30
57.49
64.30
64.14
63.22
63.14
64.13
63.98
69.32
69.16
64.05
63.98
64.61
64.76
69.52
69.66
57.49
57.65
58.45
58.61
64.42
64.26
66.20
66.01
66.50
66.64
66.71
64.56
4.99
5.17
5.33
5.19
4.70
4.52
4.69
4.87
5.11
4.94
4.99
4.87
5.35
5.19
5.39
5.21
4.03
3.90
4.10
4.24
4.49
4.40
4.21
4.38
4.99
4.82
5.10
4.92
4.35
4.18
4.70
4.56
4.82
4.69
4.72
4.56
5.08
4.92
4.82
4.98
3.41
3.56
4.02
3.93
4.22
4.15
5.11
5.30
5.74
5.59
4.91
4.97
21.30
21.13
17.43
17.19
18.12
18.46
17.70
17.80
14.80
14.91
18.01
17.80
17.05
17.19
14.59
14.48
16.70
16.92
16.60
16.37
13.71
13.90
23.05
23.39
22.20
22.35
17.75
17.98
19.21
19.38
18.50
18.65
15.77
15.51
18.41
18.65
18.20
17.98
15.31
15.04
17.79
17.69
17.00
17.09
14.65
14.41
13.21
13.39
12.71
12.95
12.42
12.55
9.92
9.68
8.06
7.87
8.59
8.45
7.91
8.15
6.62
6.83
8.29
8.15
8.06
7.87
6.59
6.63
7.50
7.75
7.70
7.49
6.21
6.35
10.98
10.71
9.99
10.23
8.05
8.23
9.05
8.87
8.42
8.54
7.34
7.10
8.39
8.54
8.09
8.23
7.05
6.89
8.00
8.10
7.91
7.82
6.85
6.60
7.84
7.66
7.64
7.41
7.33
7.18
C15H17N5O2S
C21H21N5O2S
C19H17N5O2S
C20H19N5O2S
C26H23N5O2S
C20H19N5O2S
C21H21N5O2S
C27H25N5O2S
C19H16ClN5O2S
C20H18ClN5O2S
C26H22ClN5O2S
C14H13N5OS
C15H15N5OS
C21H19N5OS
C19H15N5OS
C20H17N5OS
C26H21N5OS
C20H17N5OS
C21H19N5OS
C27H23N5OS
C19H14ClN5OS
C20H16ClN5OS
C26H20ClN5OS
C23H22N4O2S
C24H24N4O2S
C24H22N4O3S
—
—
—
—
—
—
—
4g
4h
4i
139—140
271—272
>300
4j
135—136
266—268
>300
8.40
8.57
8.51
8.29
7.24
7.03
—
4k
4l
5а
5b
5c
5d
5e
5f
290—292
>300
—
—
—
—
—
—
—
—
>300
>300
>300
>300
5g
5h
5i
>300
>300
>300
5j
>300
8.71
8.96
8.51
8.65
7.02
7.29
—
5k
5l
>300
>300
5p
5q
5r
143—145
164—165
171—173
—
—
(to be continued)

2296
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 10, October, 2004
Eltsov et al.
Table 1 (continued)
Comꢀ Yield
pound (%)
M.p.
/°C
Found
Calculated
Molecular
formula
(%)
C
H
N
S
Cl
—
5s
45
50
34
47
53
40
57
52
88
80
82
80
41
41
89
62
63
71
52
50
60
65
68
71
162—163
152—153
205—206
165—167
179—180
209—211
172—173
183—185
209—210
163—165
207—208
205—206
185—186
218—219
192—193
190—191
183—184
178—180
258—260
249—251
229—231
205—206
165—166
173—174
66.48
66.64
67.12
67.24
65.34
65.20
61.14
60.99
61.58
61.73
59.81
59.93
53.80
53.96
55.30
55.43
55.28
55.43
56.89
56.76
63.21
63.30
64.28
64.10
55.78
55.64
56.74
56.81
56.99
56.81
57.71
57.89
63.60
63.43
64.00
64.12
59.50
59.36
60.68
60.60
58.79
58.70
59.65
59.80
59.95
59.80
60.69
60.82
5.64
5.59
6.05
5.87
5.15
5.25
4.80
4.67
4.90
4.96
4.55
4.40
5.40
5.23
5.48
5.65
5.50
5.65
5.89
6.03
5.72
5.58
6.02
5.89
5.71
5.54
5.80
5.89
5.69
5.89
6.09
6.21
5.91
5.79
5.89
6.05
4.49
4.63
5.18
5.09
5.09
5.23
5.78
5.61
5.58
5.61
5.87
5.95
12.69
12.95
12.79
12.55
12.39
12.16
12.64
12.37
11.89
12.00
11.79
11.65
24.42
24.20
23.19
23.08
23.28
23.08
21.95
22.06
18.28
18.45
17.98
17.80
20.20
20.27
19.75
19.48
19.79
19.48
18.92
18.75
16.22
16.08
15.88
15.58
24.49
24.72
23.81
23.55
21.22
21.39
20.72
20.51
20.75
20.51
19.89
19.70
7.54
7.41
7.38
7.18
7.15
6.96
7.00
7.08
7.06
6.87
6.33
6.67
11.23
11.08
10.80
10.57
10.77
10.57
10.33
10.10
8.59
8.45
7.99
8.15
9.41
9.28
8.61
8.92
8.99
8.92
8.45
8.59
7.55
7.36
7.01
7.13
—
C24H24N4O2S
C25H26N4O2S
C25H24N4O3S
C23H21ClN4O2S
C24H23ClN4O2S
C24H21ClN4O3S
C13H15N5OS
C14H17N5OS
C14H17N5OS
C15H19N5OS
C20H21N5OS
C21H23N5OS
C16H19N5O2S
C17H21N5O2S
C17H21N5O2S
C18H23N5O2S
C23H25N5O2S
C24H27N5O2S
C14H13N5O2
C15H15N5O2
C16H17N5OS
C17H19N5OS
C17H19N5OS
C18H21N5OS
5t
—
—
5u
5v
7.99
7.83
7.78
7.59
7.11
7.37
—
5w
5x
8а
8b
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
8c
8d
8e
8f
9a
9b
9c
9d
9e
9f
10a
10b
11a
11b
11c
11d
—
9.64
9.79
9.11
9.39
9.24
9.39
9.00
9.02
Note. Imidazolylthiazolines 5m—o were described earlier.4

Synthesis of novel 2ꢀ(azolylimino)thiazolines
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 10, October, 2004
2297
Table 2. 1H NMR and mass spectra of the compounds obtained
Comꢀ
pound
δ (J/Hz)
m/z
[M]+
2a
2b
7.13—7.69 (m, 8 H, Ph, CONH2); 7.34 (s, 1 H, CH, Im); 10.10, 12.43 (both br.s, 1 H each, 2 NH)
2.83 (d, 3 Н, NHMe, J = 4.6); 7.12—7.74 (m, 6 H, Ph, NH); 7.76 (s, 1 H, CH, Im);
10.11, 10.41 (both br.s, 1 H each, 2 NH)
261
275
2c
2d
4а
4b
4c
2.31 (s, 1 H, Me); 7.09—7.56 (AA´BB´, 4 Н, Ar, J = 8.2); 7.17—7.80 (m, 5 H, Ph);
7.83 (s, 1 H, CH, Im); 9.58, 10.11, 12.46, 12.85 (all br.s, 1 H each, 4 NH)
1.35 (t, 3 H, OCH2Me, J = 7.0); 4.37 (q, 2 H, OCH2Me, J = 7.0); 7.20—7.68 (m, 5 H, Ph);
7.95 (s, 1 Н, СН, Im); 9.19, 12.43, 13.53 (all br.s, 1 H each, 3 NH)
1.40 (s, 3 Н, Me); 3.17—3.32 (AB, 2 Н, СН2, J = 11.4); 6.30 (s, 1 Н, OН); 6.37, 6.93 (both br.s,
1 H each, CONH2); 7.36 (s, 1 Н, СH, Im); 7.32—7.44 (m, 5 Н, Ph); 12.25 (br.s, 1 Н, NH, Im)
1.41 (s, 3 Н, Me); 2.35 (d, 3 Н, NHMe, J = 4.9); 3.28—3.49 (AB, 2 Н, СН2, J = 11.4);
7.39 (s, 1 Н, СH, Im); 7.33—7.50 (m, 7 Н, Ph, OH, NHMe); 12.28 (br.s, 1 Н, NH, Im)
1.35, 2.24 (both s, 3 H each, 2 Me); 3.26—3.45 (AB, 2 Н, СН2, J = 11.4); 6.35 (s, 1 Н, OH);
6.54—6.89 (АА´ВВ´, 4 H, Ar, J = 8.2); 7.44—7.46 (m, 6 Н, Ph, CH, Im); 9.51 (br.s, 1 Н, NH);
12.46 (br.s, 1 Н, NH, Im)
351
290
317
331
407
4d
4e
4f
3.45—3.65 (AB, 2 Н, СН2, J = 11.9); 6.47, 7.01 (both br.s, 1 H each, CONH2); 7.42 (s, 1 Н, СH, Im);
7.04—7.56 (both m, 5 H each, 2 Ph); 7.55 (s, 1 Н, ОН); 12.31 (br.s, 1 Н, NH, Im)
2.36 (d, 3 Н, NHMe, J = 4.9); 3.44—3.70 (AB, 2 Н, СН2, J = 11.6); 7.39 (s, 1 Н, СH, Im);
7.10—7.56 (m, 11 Н, 2 Ph, OH); 7.46 (br.s, 1 Н, NНMe); 12.37 (br.s, 1 Н, NH, Im)
2.21 (s, 3 Н, Me); 3.49—3.75 (AB, 2 Н, СН2, J = 11.9); 6.53—6.82 (АА´ВВ´, 4 H, Ar, J = 8.2);
7.15—7.56 (m, 11 Н, 2 Ph, OH); 7.52 (s, 1 Н, СH, Im); 9.52 (br.s, 1 Н, NH); 12.55 (br.s, 1 Н, NH, Im)
2.24 (s, 3 Н, Me); 3.40—3.65 (AB, 2 Н, СН2, J = 11.9); 6.47 (br.s, 1 Н, СONH2); 6.99—7.07 (m, 5 H, Ar,
CONH2); 7.23—7.45 (m, 5 Н, Ph); 7.50 (s, Н, CH, Im); 12.32 (br.s, 1 Н, NH, Im)
2.24 (s, 3 Н, Me); 3.43—3.69 (AB, 2 Н, СН2, J = 11.9); 7.03 (d, 2 Н, Ar, J = 7.9);
7.12—7.48 (m, 10 Н, Ar, OH, CH, Im); 12.36 (br.s, 1 Н, NH, Im)
379
393
469
393
407
483
4g
4h
4i
2.22, 2.24 (both s, 3 H each, 2 Me); 3.44—3.71 (AB, 2 Н, СН2, J = 11.9); 6.52—6.85 (АА´ВВ´, 4 H, Ar,
J = 8.2); 7.01—7.40 (АА´ВВ´, 4 H, Ar, J = 7.9); 7.12—7.29 (m, 6 Н, Ph, OH); 7.51 (s, 1 Н, СH, Im);
9.52, 12.55 (both br.s, 1 H each, 2 NH)
4j
3.44—3.68 (AB, 2 Н, СН2, J = 11.9); 6.49, 6.99 (both br.s, 1 H each, CONH2); 7.04—7.28 (m, 7 Н, Ar);
7.34, 7.42 (both s, 1 H each, ОН, CH, Im); 7.56 (d, 2 H, Ar, J = 8.6); 12.36 (br.s, 1 Н, NH, Im)
2.38 (d, 3 Н, NHMe, J = 4.9); 3.45—3.70 (AB, 2 Н, СН2, J = 11.9); 7.15—7.31 (m, 9 Н, Ar, NHMe);
7.32, 7.39 (both s, 1 H each, ОН, CH, Im); 7.56 (d, 2 H, Ar, J = 8.8); 12.38 (br.s, 1 Н, NH, Im)
2.22 (s, 3 Н, Me); 3.47—3.74 (AB, 2 Н, СН2, J = 11.6); 6.52—6.83 (АА´ВВ´, 4 H, Ar, J = 8.2);
7.51 (s, 1 Н, CH, Im); 7.34—7.54 (m, 10 H, Ar, ОН); 9.49, 12.57 (both br.s, 1 H each, 2 NH)
1.93 (d, 3 Н, Me, J = 0.9); 6.41, 6.96 (both br.s, 1 H each, CONH2); 6.16 (br.s, 1 Н, СHthiazol);
7.34—7.58 (m, 5 Н, Ph); 7.43 (s, 1 Н, СH, Im); 12.31 (br.s, 1 Н, NH, Im)
1.95 (d, 3 Н, Me, J = 0.9); 2.39 (d, 3 Н, NHMe, J = 4.6); 6.16 (br.s, 1 Н, СHthiazol); 7.57 (s, 1 Н,
СH, Im); 7.34—7.58 (m, 6 Н, Ph, NHMe); 12.32 (br.s, 1 Н, NH, Im);
1.95, 2.25 (both s, 3 H each, 2 Me); 6.21 (br.s, 1 Н, CHthiazol); 6.57—6.87 (АА´ВВ´, 4 H, Ar, J = 7.9);
7.38—7.77 (m, 6 Н, Ph, CH, Im); 9.54 (br.s, 1 Н, NH); 12.52 (br.s, 1 Н, NH, Im);
6.61, 7.04 (both br.s, 1 H each, CONH2); 7.16—7.40 (both m, 5 H each, 2 Ph); 6.58, 7.42 (both s, 1 H each,
СНthiazol, СH, Im); 12.40 (br.s, 1 Н, NH, Im)
2.45 (d, 3 Н, NHMe, J = 4.9); 7.18—7.50 (m, 11 Н, 2 Ph, NHMe); 6.65, 7.52 (both s, 1 H each, СНthiazol
СH, Im); 12.46 (br.s, 1 Н, NH, Im)
2.24 (s, 3 Н, Me); 6.60—6.88 (АА´ВВ´, 4 H, Ar, J = 8.2); 7.07—7.43 (both m, 5 H each, 2 Ph);
6.58, 7.57 (both s, 1 H each, CH, Im, CHthiazol); 9.47, 12.59 (both br.s, 1 H each, NH)
2.24 (s, 3 Н, Me); 6.61 (s, 1 Н, СONH2); 6.99—7.07 (m, 5 H, Ar, CONH2); 7.22—7.42 (m, 5 Н, Ph);
6.53, 7.51 (both s, 1 H each, CHthiazol, CH, Im); 12.39 (br.s, 1 Н, NH, Im)
413
427
503
299
313
389
361
375
451
375
389
465
4k
4l
5а
5ba
5c
5d
5e
5f
,
5g
5h
5i
2.24 (s, 3 Н, Me); 2.45 (d, 3 Н, NHMe, J = 4.9); 6.99—7.09 (АА´ВВ´, 4 H, Ar, J = 8.2);
6.56, 7.50 (both s, 1 H each, CHthiazol, CH, Im); 7.27—7.53 (m, 6 Н, Ph, NHMe); 12.42 (br.s, 1 Н, NH, Im)
2.23, 2.24 (both s, 3 H each, 2 Me); 6.61—6.90 (АА´ВВ´, 4 H, Ar, J = 8.2); 6.93—7.01 (m, 4 Н, Ar);
7.01—7.43 (m, 5 Н, Ph); 6.54, 7.59 (both s, 2 Н, СНthiazol, СH, Im); 9.47 (br.s, 1 Н, NH);
12.59 (br.s, 1 Н, NH, Im)
5j
6.61, 7.02 (both br.s, 1 H each, CONH2); 7.15—7.53 (m, 9 H, Ar); 6.64, 7.50 (both s, 1 H each, СНthiazol
,
395
СH, Im); 12.40 (br.s, 1 Н, NH, Im)
(to be continued)

2298
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 10, October, 2004
Eltsov et al.
Table 2 (continued)
Comꢀ
pound
δ (J/Hz)
m/z
[M]+
5k
5lb
5p
5q
2.46 (d, 3 Н, NHMe, J = 4.9); 6.62, 7.46 (both s, 1 H each, СНthiazol, CH, Im); 7.15—7.59 (m, 10 Н, Ar,
NHMe); 12.43 (br.s, 1 Н, NH, Im)
409
485
418
432
2.23 (s, 3 Н, Me); 6.60—6.91 (АА´ВВ´, 4 H, Ar, J = 8.2); 6.68, 7.61 (both s, 1 H each, СНthiazol, CH, Im);
7.10—7.23 (АА´ВВ´, 4 H, Ar, J = 8.6); 7.35—7.45 (m, 5 H, Ph); 9.45, 12.63 (both br.s, 1 H each, NH)
1.04, 1.36 (both t, 3 H each, OCH2Me, NCH2Me, J = 7.2); 4.11, 4.27 (both q, 2 H each, OCH2Me,
NCH2Me, J = 7.2); 6.25 (s, 1 H, CHthiazol); 7.07—7.34 (both m, 5 H each, 2 Ph); 7.48 (s, 1 H, CH, Im)
0.87 (t, 3 Н, NСH2CH2Me, J = 7.3); 1.04 (t, 3 H, OCH2Me, J = 7.0); 1.76 (tq, 2 H, NCH2CH2Me,
J´ = 7.0, J″ = 7.3); 4.12, 4.19 (both q, 2 H each, NCH2CH2Me, OCH2Me, J = 7.0); 6.26 (s, 1 H, CHthiazol);
7.10—7.34 (both m, 5 H each, 2 Ph); 7.46 (s, 1 H, CH, Im)
5r
5s
1.03 (t, 3 H, OCH2Me, J = 7.3); 2.22 (s, 3 H, NCH2COMe); 4.08 (q, 2 H, OCH2Me, J = 7.3); 5.07 (s, 2 H,
NCH2COMe); 6.43 (s, 1 H, CHthiazol); 7.12—7.44 (both m, 5 H each, 2 Ph); 7.69 (s, 1 H, CH, Im)
1.04 (t, 3 H, OCH2Me, J = 7.2); 1.36 (t, 3 H, NCH2Me, J = 7.0); 2.26 (s, 3 H, Me);
4.09 (q, 2 H, OCH2Me, J = 7.2); 4.26 (q, 2 H, NCH2Me, J = 7.0); 6.20 (s, 1 H, CHthiazol);
6.90—7.00 (m, 4 H, Ar); 7.25—7.35 (m, 5 H, Ph); 7.47 (s, 1 H, CH, Im)
446
432
5t
0.87 (t, 3 Н, NСH2CH2Me, J = 7.3); 1.03 (t, 3 H, OCH2Me, J = 7.0); 1.75 (tq, 2 H, NCH2CH2Me,
J´ = 7.0, J″ = 7.3); 2.26 (s, 3 H, Me); 4.09 (q, 2 H, OCH2Me, J = 7.0); 4.18 (t, 2 H, NCH2CH2Me,
J = 7.0); 6.21 (s, 1 H, CHthiazol); 6.92—7.00 (m, 4 H, Ar); 7.24—7.34 (m, 5 H, Ph); 7.45 (s, 1 H, CH, Im)
1.02 (t, 3 H, OCH2Me, J = 7.3); 2.22, 2.27 (both s, 3 H each, Me, NCH2COMe); 4.08 (q, 2 H, OCH2Me,
J = 7.3); 5.07 (s, 2 H, NCH2COMe); 6.39 (s, 1 H, CHthiazol); 6.98—7.19 (m, 4 H, Ar);
7.21—7.26 (m, 5 H, Ph); 7.68 (s, 1 H, CH, Im)
1.04, 1.36 (both t, 3 H each, OCH2Me, NCH2Me, J = 7.0); 4.12, 4.27 (both q, 2 H each, NCH2CH2Me, OCH2Me, 452
J = 7.0); 6.26 (s, 1 H, CH); 7.03—7.17 (АА´ВВ´, 4 H, Ar, J = 8.5); 7.23—7.37 (m, 5 H, Ph);
7.48 (s, 1 H, CH, Im)
0.87 (t, 3 Н, NСH2CH2Me, J = 7.4); 1.03 (t, 3 H, OCH2Me, J = 7.3); 1.73 (tq, 2 H, NCH2CH2Me, J´ = 7.0,
J″ = 7.4); 4.09 (q, 2 H, OCH2Me, J = 7.3); 4.19 (t, 2 H, NCH2CH2Me, J = 7.0); 6.26 (s, 1 H, CHthiazol);
7.00—7.17 (АА´ВВ´, 4 H, Ar, J = 8.5); 7.21—7.33 (m, 5 H, Ph); 7.45 (s, 1 H, CH, Im)
1.02 (t, 3 H, OCH2Me, J = 7.0); 2.27 (s, 3 H, NCH2COMe); 4.08 (q, 2 H, OCH2Me, J = 7.0);
5.04 (s, 2 H, NCH2COMe); 6.42 (s, 1 H, CHthiazol); 7.18—7.03 (АА´ВВ´, 4 H, Ar, J = 8.1);
7.46—7.26 (m, 5 H, Ph); 7.70 (s, 1 H, CH, Im)
446
460
5u
5v
5w
5x
466
480
8а
8b
1.35 (t, 3 H, SCH2Me, J = 7.3); 2.99 (q, 2 Н, SCH2Me, J = 7.3); 7.21—7.47 (m, 5 H, Ph);
6.20, 8.70 (both br.s, 1 H each, CONH2); 7.51 (s, 1 H, CH, Im); 11.83, 12.36 (both br.s, 1 H each, 2 NH)
0.96 (t, 3 H, SCH2CH2Me, J = 7.3); 1.70 (tq, 2 H, SCH2CH2Me, J´ = J″ = 7.3); 2.97 (t, 2 Н, SCH2CH2Me,
J = 7.3); 6.16, 8.69 (both br.s, 1 H each, CONH2); 7.27—7.40 (m, 5 H, Ph); 7.51 (s, 1 H, CH, Im);
11.83, 12.38 (both br.s, 1 H each, 2 NH)
289
303
8c
8d
1.36 (t, 3 H, SCH2Me, J = 7.6); 2.96 (q, 2 Н, SCH2Me, J = 7.6); 3.03 (d, 3 Н, NHMe, J = 4.1);
7.26—7.41 (m, 5 H, Ph); 7.49 (s, 1 H, CH, Im); 8.85 (br.s, 1 Н, NHMe); 11.76,
12.24 (both br.s, 1 H each, 2 NH)
1.05 (t, 3 H, SCH2CH2Me, J = 7.3); 1.78 (tq, 2 H, SCH2CH2Me, J´ = J″ = 7.3); 3.00 (t, 2 Н,
SCH2CH2Me, J = 7.3); 3.03 (d, 3 Н, NHMe, J = 4.9); 7.28—7.41 (m, 5 H, Ph); 7.49 (s, 1 H, CH, Im);
8.81 (br.s, 1 Н, NHMe); 11.79, 12.30 (both br.s, 1 H each, 2 NH)
303
317
8e
8f
1.32 (t, 3 H, SCH2Me, J = 7.3); 2.30 (s, 3 H, Me); 3.14 (q, 2 Н, SCH2Me, J = 7.3); 7.10 (d, 2 Н, Ar,
J = 8.2); 7.20—7.45 (m, 7 H, Ph, Ar); 7.58 (s, 1 H, CH, Im); 10.23, 12.07, 12.93 (all br.s, 1 H each, 3 NH)
0.99 (t, 3 H, SCH2CH2Me, J = 7.3); 1.70 (tq, 2 H, SCH2CH2Me, J´ = J″ = 7.3); 3.16 (t, 2 Н,
SCH2CH2Me, J = 7.3); 7.12—7.46 (m, 5 H, Ph); 7.12—7.54 (АА´ВВ´, 4 H, Ph); 7.35 (s, 1 H, CH, Im);
10.49, 11.97, 12.03 (all br.s, 1 H each, 3 NH)
379
393
9a
9b
1.33 (t, 3 H, SCH2Me, J = 7.3); 2.12 (s, 3 H, NCH2COMe); 2.98 (q, 2 Н, SCH2Me, J = 7.3); 5.13 (s, 2 H,
NCH2COMe); 5.65, 8.83 (both br.s, 1 H each, CONH2); 7.23—7.40 (m, 6 H, Ph, CH, Im); 11.71 (br.s, 1 Н, NH)
0.98 (t, 3 H, SCH2CH2Me, J = 7.3); 1.70 (tq, 2 H, SCH2CH2Me, J´ = J″ = 7.3); 2.29 (s, 3 H, NCH2COMe);
2.98 (t, 2 Н, SCH2CH2Me, J = 7.3); 5.13 (s, 2 H, NCH2COMe); 5.39, 8.80 (both br.s, 1 H each, CONH2);
7.31—7.41 (m, 5 H, Ph); 7.34 (s, 1 H, CH, Im); 11.68 (br.s, 1 Н, NH)
345
359
9c
1.38 (t, 3 H, SCH2Me, J = 7.3); 2.30 (s, 3 H, NCH2COMe); 2.90 (d, 3 Н, NHMe, J = 5.2); 2.97 (q, 2 Н,
SCH2Me, J = 7.3); 5.14 (s, 2 H, NCH2COMe); 7.36 (s, 1 H, CH, Im); 7.24—7.40 (m, 5 H, Ph);
9.09, 11.65 (both br.s, 1 H each, NHMe, NH)
359
(to be continued)

Synthesis of novel 2ꢀ(azolylimino)thiazolines
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 10, October, 2004
2299
Table 2 (continued)
Comꢀ
pound
δ (J/Hz)
m/z
[M]+
9d
9e
9f
1.05 (t, 3 H, SCH2CH2Me, J = 7.3); 1.75 (tq, 2 H, SCH2CH2Me, J´ = J″ = 7.3); 2.29 (s, 3 H, NCH2COMe);
373
435
449
2.91 (d, 3 Н, NHMe, J = 5.1); 2.99 (t, 2 Н, SCH2CH2Me, J = 7.3); 5.14 (s, 2 H, NCH2COMe);
7.32 (s, 1 H, CH, Im); 7.22—7.40 (m, 5 H, Ph); 9.04, 11.66 (both br.s, 1 H each, NH, NHMe)
1.29 (t, 3 H, SCH2Me, J = 7.2); 2.30, 2.31 (both s, 3 H each, Me, NCH2COMe); 3.12 (q, 2 Н, SCH2Me,
J = 7.2); 5.17 (s, 2 H, NCH2COMe); 7.12 (d, 2 Н, Ar, J = 8.3); 7.31 (s, 1 H, CH, Im); 7.33—7.40 (m, 7 H,
Ph, Ar); 10.71, 11.84 (both br.s, 1 H each, 2 NH)
0.95 (t, 3 H, SCH2CH2Me, J = 7.3); 1.65 (tq, 2 H, SCH2CH2Me, J´ = J″ = 7.3); 2.30 (s, 6 Н, NCH2COMe,
Me); 3.10 (t, 2 Н, SCH2CH2Me, J = 7.3); 5.14 (s, 2 H, NCH2COMe); 7.13 (d, 2 Н, Ar, J = 8,2);
7.35 (s, 1 H, CH, Im); 7.23—7.41 (m, 7 H, Ph, Ar); 11.86, 10.73 (both br.s, 1 H each, 2 NH)
2.20 (s, 3 Н, NCH2COMe); 5.18 (s, 2 H, NCH2COMe); 7.00—7.67 (m, 5 H, Ph); 7.81 (s, 1 H, CH, Im);
8.45, 10.63 (both br.s, 1 H each, 2 NН)
2.21, 3.52 (both s, 3 H each, Me, NCH2COMe); 5.19 (s, 2 H, NCH2COMe); 7.02—7.58 (m, 5 H, Ph);
7.79 (s, 1 H, CH, Im); 8.40 (br.s, 1 Н, NН)
1.36 (t, 3 Н, SCH2Me, J = 7.3); 2.11 (s, 3 Н, Me); 3.26 (q, 2 Н, SCH2Me, J = 7.3); 7.18—7.43 (m, 6 H,
Ph, NH); 6.68, 7.66 (both s, 1 H each, CH, Im, СН); 10.25 (br.s, 1 Н, NН)
1.01 (t, 3 Н, SCH2CH2Me, J = 6.7); 1.74 (tq, 2 H, SCH2CH2Me, J´ = J″ = 6.7); 2.08 (s, 3 Н, Me);
3.20 (t, 2 Н, SCH2Me, J = 6.7); 7.17—7.43 (m, 6 H, Ph, NH); 6.69, 7.67 (both s, 1 H each, СН, CH, Im);
10.21 (br.s, 1 Н, NН)
10a
10b
11a
11b
283
297
327
341
11c
11d
1.40 (t, 3 Н, SCH2Me, J = 7.3); 3.28 (q, 2 Н, SCH2Me, J = 7.3); 2.19, 3.40 (both s, 3 H each, Me, NMe);
6.67, 7.52 (both s, 1 H each, СН, CH, Im); 7.14—7.40 (m, 5 H, Ph); 11.20 (br.s, 1 Н, NН)
1.03 (t, 3 Н, SCH2CH2Me, J = 7.4); 1.75 (tq, 2 H, SCH2CH2Me, J´ = J″ = 7.4); 2.18, 3.40 (both s, 3 H each,
Me, NMe); 3.29 (m, 2 Н, SCH2CH2Me); 6.66, 7.50 (both s, 1 H each, СН, CH, Im); 7.17—7.34 (m, 5 H, Ph);
11.21 (br.s, 1 Н, NН)
341
355
a 13C NMR (100 MHz, DMSOꢀd6), δ: 14.59, 24.62, 98.44, 112.05, 128.61, 128.85, 129.59, 133.44, 133.51, 137.62, 146.16, 159.61,
160.40.
b Spectroscopic data for imidazolylthiazolines 5m—o were reported earlier.4
isothioureas 9a—f (Scheme 2). To confirm the structures
of these products, their cyclization reactions were carried
out under acidic and basic conditions. It turned out that
in the presence of 1% KOH in ethanol, they lose an
alkanethiol molecule to give purine derivatives 10a,b,
No intermolecular associates are known to form in
low concentrations in inert solvents, while intramolecular
bonds and the corresponding absorption bands in the IR
spectra are retained even in the lowest concentrations.5 In
addition, the hydrogen bonding causes a slight shift of the
absorption band to the lower frequencies.5—7
1
which were characterized by H NMR spectra. In acetic
acid, compounds 9a—f undergo cyclization into imidazoꢀ
pyrazinones 11a—d. The structures of the latter were conꢀ
firmed by their 1H NMR (δ: 6.66—6.69, s, CH) and mass
spectra containing the corresponding molecular ion peaks.
In addition, the participation of the carbamoyl group in
both cyclizations is evident from the absence of a signal
for the NH proton of the amide fragment in the 1H NMR
spectra of compounds 9a—f and 10a—d. The Me protons
in compounds 10b and 11c,d are manifested as a singlet,
in contrast to a doublet for the corresponding intermediꢀ
ates (see Table 1). The formation of compounds 11a—d
indicates that chloroacetone alkylates 5ꢀimidazolylꢀ
isothioureides 8a—f at position 3 of the imidazole ring.
To prove the configuration of the C=N bond in prodꢀ
ucts 8a—f, 9a—f, and 11a—d, a number of IR experiꢀ
ments was performed under the assumption that these
compounds can be stabilized in a fixed geometry by inꢀ
tramolecular hydrogen bonding.
In the IR spectra of compounds 8c, 9c, and 11c, the
NH stretching vibrations are manifested as the absorpꢀ
tion bands at 3460, 3260 (8c), 3440, 3270 (9c), and
3200 cm–1 (11c). Being somewhat lower than the freꢀ
quencies characteristic of amines (3500—3300 cm–1),5—7
such values suggest the presence of hydrogen bonding in
these compounds. It was found that the ν(NH) bands in
the IR spectra are virtually insensitive to a change in the
concentrations of the samples studied in CCl4 from 10–2
to 10–5 mol L–1, which allows this hydrogen bond in
compounds 8c, 9, and 11c to be regarded as intramolecuꢀ
lar. Apparently, all the products 8a—f, 9a—f, and 11a—d
are Eꢀisomers.
Thus, through the chemiselective blocking of the most
reactive site of imidazolylthiourea by alkyl residues, we
obtained and isolated 4ꢀhydroxyꢀ2ꢀimidazolyliminoꢀ
thiazolidines 4a—l and synthesized a wide range of
2ꢀimidazolyliminoꢀ∆4ꢀthiazolines 5a—x, which are strucꢀ

2300
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 10, October, 2004
Eltsov et al.
Scheme 2
tural analogs of biologically active antipyryliminothiazoꢀ
lines. The successive reactions of imidazolylthioureas
2a—c with alkyl halides and chloroacetone give (Nꢀoxoꢀ
propylimidazolyl)isothioureas 8a—f used in the synthesis
of a number of purine and imidazopyrazinone derivatives.
We found that the alkylation of 4ꢀcarbamoylimidꢀ
azolylthioureas 2 involves the sulfur atom, while the corꢀ
responding esters yield Nꢀderivatives of imidazole. This
difference can be due to the stronger electronꢀwithdrawꢀ
ing properties of the ester group.
Experimental
1
H NMR spectra were recorded on a Bruker WMꢀ250 instruꢀ
ment (250.13 MHz) in DMSOꢀd6 (1c, 4a—l, 5a—l, and 10a—b)
and CDCl3 (5p—x, 8a—f, 9a—f, and 11a—d) with Me4Si as the
1
internal standard. The 2D H—1H COSY 13C—1H HETCOR
NMR spectra of compounds 5m—o were recorded on a Bruker
DRXꢀ500 instrument (500.13 (1H) and 125.76 MHz (13C)) in
CDCl3. The signals of the solvent (δ 76.900, δ = 7.26) were
C
H
used as the internal standards. IR spectra were recorded on a
Specord IR75 instrument (KBr pellets and solutions in CCl4 in
NaCl cells (1.01 mm)). The course of the reaction was moniꢀ
tored and the purity of the products was checked by TLC on
Sorbfil UVꢀ254 plates in ethyl acetate. Mass spectra (EI, 70 eV)
were recorded on a Varian MAT 311A instrument. Meltꢀ
ing points are given uncorrected. The starting derivatives of
5ꢀaminoimidazoleꢀ4ꢀcarboxylic acid (1a, 8 1b, 9 and 1d 10) were
prepared according to known procedures.
NꢀpꢀTolylꢀ5ꢀaminoimidazoleꢀ4ꢀcarboxamide hydrochloride
1c was synthesized as described below by reduction of the correꢀ
sponding nitro derivative prepared from 5ꢀnitroimidazoleꢀ4ꢀ
carboxylic acid.11
8, 9, 11 R1
R3
R4
8, 9
R1
R3
a
b
c
d
NH2
NH2
NHMe
NHMe
Et
Pr
Et
Pr
H
H
Me
Me
e
f
NHC6H4Meꢀp
NHC6H4Meꢀp
Et
Pr
NꢀpꢀTolylꢀ5ꢀnitroimidazoleꢀ4ꢀcarboxamide. Phosphorus
pentachloride (13.28 g, 0.064 mol) was added to a solution of
5ꢀnitroimidazoleꢀ4ꢀcarboxylic acid (10 g, 0.064 mol) in 100 mL
of anhydrous benzene. The reaction mixture was refluxed for
1.5 h in a water bath and cooled to ~20 °C. pꢀToluidine
(0.076 mol) was added and the resulting mixture was kept in a
water bath for 2 h and then cooled. The precipitate that formed
was filtered off and recrystallized from ethanol. The yield of the
target product was 82%, m.p. 293—295 °C. Found (%): C, 53.50;
H, 4.11; N, 23.03. C11H10N4O3. Calculated (%): C, 53.66;
10: R4 = H (a), Me (b)
1
H, 4.09; N, 22.75. H NMR, δ: 2.32 (s, 3 H, Me); 7.14—7.55
(AA´BB´, 4 H, Ar, J = 8.2 Hz); 7.77 (s, 1 H, CH, Im); 10.58
(s, 1 H, NH); 13.75 (br.s, 1 H, NH). MS, m/z (Irel (%)):
246 [M]+ (100).
NꢀpꢀTolylꢀ5ꢀaminoimidazoleꢀ4ꢀcarboxamide hydrochloride
(1c). Nꢀ(pꢀTolyl)ꢀ5ꢀnitroimidazoleꢀ4ꢀcarboxamide (0.04 mol)
was added in portions at 0 to 5 °C to a stirred cooled solution of
SnCl2•2H2O (46 g, 0.2 mol) in 200 mL of conc. HCl. The
reaction mixture was kept for 24 h with gradual warming to
room temperature. The precipitate was filtered off and dissolved
in 400 mL of water. Hydrogen sulfide was passed through the
resulting solution to complete precipitation of tin sulfide, which
was filtered off. The filtrate was lightened with activated carbon
and evaporated to dryness in vacuo. The residue was recrysꢀ
tallized from ethanol to give compound 1c in 70% yield,
m.p. 193—195 °C. Found (%): C, 52.10; H, 5.11; N, 21.82.

Synthesis of novel 2ꢀ(azolylimino)thiazolines
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 10, October, 2004
2301
C11H12N4O•HCl. Calculated (%): C, 52.28; H, 5.19; N, 22.17.
1H NMR, δ: 2.29 (s, 3 H, Me); 6.34 (br.s, 2 H, NH2); 7.07—7.67
(AA´BB´, 4 H, Ar, J = 8.2 Hz); 8.62 (s, 1 H, CH, Im); 10.53
(s, 1 H, NH); 14.18 (br.s, 1 H, NH). MS, m/z (Irel (%)):
216 [M]+ (85).
5ꢀ(3ꢀPhenylthioureido)ꢀ3Hꢀimidazoleꢀ4ꢀcarboxamide (2a),
Nꢀmethylꢀ5ꢀ(3ꢀphenylthioureido)ꢀ3Hꢀimidazoleꢀ4ꢀcarboxamide
(2b), and Nꢀpꢀtolylꢀ5ꢀ(3ꢀphenylthioureido)ꢀ3Hꢀimidazoleꢀ4ꢀ
carboxamide (2c). Triethylamine (1.03 g, 10.2 mmol) and pheꢀ
nyl isothiocyanate (0.46 g, 3.4 mmol) were added to a solution
of the corresponding hydrochloride 1a—c (2.8 mmol) in 5 mL of
DMSO. The reaction mixture was kept at ~20 °C for 12 h. Water
(50—100 mL) was added and the precipitate of imidazolyl(pheꢀ
nyl)thiourea that formed was filtered off. The precipitate was
suspended in ethyl acetate, filtered off, and dried.
Ethyl 5ꢀ(3ꢀphenylthioureido)ꢀ3Hꢀimidazoleꢀ4ꢀcarboxylate
(2d). Phenyl isothiocyanate (3.1 mmol) was added to a solution
of ethyl 5ꢀaminoimidazoleꢀ4ꢀcarboxylate hydrochloride (1d)
(2.6 mmol) in 6 mL of pyridine. The reaction mixture was kept
at 60 °C for 1 h and cooled. Water (50 mL) was added and the
precipitate of imidazolyl(phenyl)thiourea that formed was filꢀ
tered off and recrystallized from ethanol.
5ꢀ(4ꢀHydroxyꢀ4ꢀmethylꢀ3ꢀphenylthiazolidinꢀ2Zꢀylideneꢀ
amino)ꢀ3Hꢀimidazoleꢀ4ꢀcarboxamide (4a), Nꢀmethylꢀ5ꢀ(4ꢀhydrꢀ
oxyꢀ4ꢀmethylꢀ3ꢀphenylthiazolidinꢀ2Zꢀylideneamino)ꢀ3Hꢀimidꢀ
azoleꢀ4ꢀcarboxamide (4b), Nꢀpꢀtolylꢀ5ꢀ(4ꢀhydroxyꢀ4ꢀmethylꢀ3ꢀ
phenylthiazolidinꢀ2Zꢀylideneamino)ꢀ3Hꢀimidazoleꢀ4ꢀcarboxamide
(4c), 5ꢀ(4ꢀhydroxyꢀ3,4ꢀdiphenylthiazolidinꢀ2Zꢀylideneamino)ꢀ
3Hꢀimidazoleꢀ4ꢀcarboxamide (4d), Nꢀmethylꢀ5ꢀ(4ꢀhydroxyꢀ3,4ꢀ
diphenylthiazolidinꢀ2Zꢀylideneamino)ꢀ3Hꢀimidazoleꢀ4ꢀcarboxꢀ
amide (4e), Nꢀpꢀtolylꢀ5ꢀ(4ꢀhydroxyꢀ3,4ꢀdiphenylthiazolidinꢀ2Zꢀ
ylideneamino)ꢀ3Hꢀimidazoleꢀ4ꢀcarboxamide (4f), 5ꢀ(4ꢀhydroxyꢀ
3ꢀphenylꢀ4ꢀpꢀtolylthiazolidinꢀ2Zꢀylideneamino)ꢀ3Hꢀimidazoleꢀ4ꢀ
carboxamide (4g), Nꢀmethylꢀ5ꢀ(4ꢀhydroxyꢀ3ꢀphenylꢀ4ꢀpꢀtolylꢀ
thiazolidinꢀ2Zꢀylideneamino)ꢀ3Hꢀimidazoleꢀ4ꢀcarboxamide (4h),
Nꢀpꢀtolylꢀ5ꢀ(4ꢀhydroxyꢀ3ꢀphenylꢀ4ꢀpꢀtolylthiazolidinꢀ2Zꢀylꢀ
ideneamino)ꢀ3Hꢀimidazoleꢀ4ꢀcarboxamide (4i), 5ꢀ[4ꢀ(4ꢀchloroꢀ
phenyl)ꢀ4ꢀhydroxyꢀ3ꢀphenylthiazolidinꢀ2Zꢀylideneamino]ꢀ3Hꢀ
imidazoleꢀ4ꢀcarboxamide (4j), Nꢀmethylꢀ5ꢀ[4ꢀ(4ꢀchlorophenyl)ꢀ
4ꢀhydroxyꢀ3ꢀphenylthiazolidinꢀ2Zꢀylideneamino]ꢀ3Hꢀimidazoleꢀ
4ꢀcarboxamide (4k), and Nꢀpꢀtolylꢀ5ꢀ[4ꢀ(4ꢀchlorophenyl)ꢀ4ꢀ
hydroxyꢀ3ꢀphenylthiazolidinꢀ2Zꢀylideneamino]ꢀ3Hꢀimidazoleꢀ4ꢀ
carboxamide (4l). Triethylamine (0.76 mmol) and the correꢀ
sponding haloketone (0.76 mmol) were added to a solution of
5ꢀimidazolyl(phenyl)thiourea 2a—c (0.69 mmol) in 2 mL
of DMF. The reaction mixture was kept at ~20 °C for 1 to 2 h.
Water (30 mL) was added and the precipitate of hydroxy(imidꢀ
azolyl)thiazolidines that formed was filtered off, washed with
ethanol, and dried.
ylideneamino)ꢀ3Hꢀimidazoleꢀ4ꢀcarboxamide (5h), Nꢀpꢀtolylꢀ5ꢀ
(3ꢀphenylꢀ4ꢀpꢀtolylꢀ3Hꢀthiazolꢀ2Zꢀylideneamino)ꢀ3Hꢀimidazoleꢀ
4ꢀcarboxamide (5i), 5ꢀ[4ꢀ(4ꢀchlorophenyl)ꢀ3ꢀphenylꢀ3Hꢀthiazolꢀ
2Zꢀylideneamino]ꢀ3Hꢀimidazoleꢀ4ꢀcarboxamide (5j), Nꢀmethylꢀ
5ꢀ[4ꢀ(4ꢀchlorophenyl)ꢀ3ꢀphenylꢀ3Hꢀthiazolꢀ2Zꢀylideneamino]ꢀ
3Hꢀimidazoleꢀ4ꢀcarboxamide (5k), and Nꢀpꢀtolylꢀ5ꢀ[4ꢀ(4ꢀchloroꢀ
phenyl)ꢀ3ꢀphenylꢀ3Hꢀthiazolꢀ2Zꢀylideneamino]ꢀ3Hꢀimidazoleꢀ4ꢀ
carboxamide (5l). A solution or suspension of compound 4a—l
(0.70 mmol) in 5 mL of AcOH was refluxed for 1 to 4 h. The
reaction mixture was diluted with cold water (30 mL) and the
precipitates of compounds 5a—l were filtered off.
Ethyl 3ꢀethylꢀ5ꢀ(3,4ꢀdiphenylꢀ3Hꢀthiazolꢀ2Zꢀylideneamino)ꢀ
3Hꢀimidazoleꢀ4ꢀcarboxylate (5p), ethyl 5ꢀ(3,4ꢀdiphenylꢀ3Hꢀ
thiazolꢀ2Zꢀylideneamino)ꢀ3ꢀpropylꢀ3Hꢀimidazoleꢀ4ꢀcarboxylate
(5q), ethyl 5ꢀ(3,4ꢀdiphenylꢀ3Hꢀthiazolꢀ2Zꢀylideneamino)ꢀ3ꢀ
(2ꢀoxopropyl)ꢀ3Hꢀimidazoleꢀ4ꢀcarboxylate (5r), ethyl 3ꢀethylꢀ
5ꢀ(3ꢀphenylꢀ4ꢀpꢀtolylꢀ3Hꢀthiazolꢀ2Zꢀylideneamino)ꢀ3Hꢀimidꢀ
azoleꢀ4ꢀcarboxylate (5s), ethyl 5ꢀ(3ꢀphenylꢀ4ꢀpꢀtolylꢀ3Hꢀthiazolꢀ
2Zꢀylideneamino)ꢀ3ꢀpropylꢀ3Hꢀimidazoleꢀ4ꢀcarboxylate (5t),
ethyl
3ꢀ(2ꢀoxopropyl)ꢀ5ꢀ(3ꢀphenylꢀ4ꢀpꢀtolylꢀ3Hꢀthiazolꢀ
2Zꢀylideneamino)ꢀ3Hꢀimidazoleꢀ4ꢀcarboxylate (5u), ethyl
5ꢀ[4ꢀ(4ꢀchlorophenyl)ꢀ3ꢀphenylꢀ3Hꢀthiazolꢀ2Zꢀylideneamino]ꢀ3ꢀ
ethylꢀ3Hꢀimidazoleꢀ4ꢀcarboxylate (5v), ethyl 5ꢀ[4ꢀ(4ꢀchloroꢀ
phenyl)ꢀ3ꢀphenylꢀ3Hꢀthiazolꢀ2Zꢀylideneamino]ꢀ3ꢀpropylꢀ3Hꢀ
imidazoleꢀ4ꢀcarboxylate (5w), and ethyl 5ꢀ[4ꢀ(4ꢀchlorophenyl)ꢀ
3ꢀphenylꢀ3Hꢀthiazolꢀ2Zꢀylideneamino]ꢀ3ꢀ(2ꢀoxopropyl)ꢀ3Hꢀ
imidazoleꢀ4ꢀcarboxylate (5x). Triethylamine (0.76 mmol) and
the corresponding haloketone (0.76 mmol) were added to soluꢀ
tions of Nꢀalkylimidazole derivatives 7a—c (0.69 mmol) in 2 mL
of DMF. The reaction mixture was kept at ~20 °C for 10 h.
Water (30 mL) was added and the precipitate that formed was
filtered off and dried. The isolated product was dissolved in
5 mL of AcOH, kept at 70 °C for 0.5 h, and concentrated. The
residue was crystallized from aqueous ethanol to give comꢀ
pounds 5p—x.
5ꢀ(2ꢀEthylꢀ3ꢀphenylꢀEꢀisothioureido)ꢀ3Hꢀimidazoleꢀ4ꢀ
carboxamide (8a), 5ꢀ(3ꢀphenylꢀ2ꢀpropylꢀEꢀisothioureido)ꢀ3Hꢀ
imidazoleꢀ4ꢀcarboxamide (8b), Nꢀmethylꢀ5ꢀ(2ꢀethylꢀ3ꢀphenylꢀEꢀ
isothioureido)ꢀ3Hꢀimidazoleꢀ4ꢀcarboxamide (8c), Nꢀmethylꢀ5ꢀ
(3ꢀphenylꢀ2ꢀpropylꢀEꢀisothioureido)ꢀ3Hꢀimidazoleꢀ4ꢀcarboxꢀ
amide (8d), Nꢀpꢀtolylꢀ5ꢀ(2ꢀethylꢀ3ꢀphenylꢀEꢀisothioureido)ꢀ3Hꢀ
imidazoleꢀ4ꢀcarboxamide (8e), and Nꢀpꢀtolylꢀ5ꢀ(3ꢀphenylꢀ2ꢀproꢀ
pylꢀEꢀisothioureido)ꢀ3Hꢀimidazoleꢀ4ꢀcarboxamide (8f). Triethylꢀ
amine (0.76 mmol) and alkyl halide (0.76 mmol) were added to
a solution of 5ꢀimidazolyl(phenyl)thiourea 2a—c (0.69 mmol)
in 2 mL of DMF. The reaction mixture was kept at ~20 °C
for 8 to 12 h and diluted with water. The precipitates of comꢀ
pounds 8 that formed were filtered off and crystallized from
ethanol.
5ꢀ(4ꢀMethylꢀ3ꢀphenylꢀ3Hꢀthiazolꢀ2Zꢀylideneamino)ꢀ3Hꢀ
imidazoleꢀ4ꢀcarboxamide (5a), Nꢀmethylꢀ5ꢀ(4ꢀmethylꢀ3ꢀphenylꢀ
3Hꢀthiazolꢀ2Zꢀylideneamino)ꢀ3Hꢀimidazoleꢀ4ꢀcarboxamide (5b),
Nꢀpꢀtolylꢀ5ꢀ(4ꢀmethylꢀ3ꢀphenylꢀ3Hꢀthiazolꢀ2Zꢀylideneamino)ꢀ
3Hꢀimidazoleꢀ4ꢀcarboxamide (5c), 5ꢀ(3,4ꢀdiphenylꢀ3Hꢀthiazolꢀ
2Zꢀylideneamino)ꢀ3Hꢀimidazoleꢀ4ꢀcarboxamide (5d), Nꢀmethylꢀ
5ꢀ(3,4ꢀdiphenylꢀ3Hꢀthiazolꢀ2Zꢀylideneamino)ꢀ3Hꢀimidazoleꢀ4ꢀ
carboxamide (5e), Nꢀpꢀtolylꢀ5ꢀ(3,4ꢀdiphenylꢀ3Hꢀthiazolꢀ2Zꢀ
ylideneamino)ꢀ3Hꢀimidazoleꢀ4ꢀcarboxamide (5f), 5ꢀ(3ꢀphenylꢀ4ꢀ
pꢀtolylꢀ3Hꢀthiazolꢀ2Zꢀylideneamino)ꢀ3Hꢀimidazoleꢀ4ꢀcarboxꢀ
amide (5g), Nꢀmethylꢀ5ꢀ(3ꢀphenylꢀ4ꢀpꢀtolylꢀ3Hꢀthiazolꢀ2Zꢀ
5ꢀ(2ꢀEthylꢀ3ꢀphenylꢀEꢀisothioureido)ꢀ3ꢀ(2ꢀoxopropyl)ꢀ3Hꢀ
imidazoleꢀ4ꢀcarboxamide (9a), 3ꢀ(2ꢀoxopropyl)ꢀ5ꢀ(3ꢀphenylꢀ
2ꢀpropylꢀEꢀisothioureido)ꢀ3Hꢀimidazoleꢀ4ꢀcarboxamide (9b),
Nꢀmethylꢀ5ꢀ(2ꢀethylꢀ3ꢀphenylꢀEꢀisothioureido)ꢀ3ꢀ(2ꢀoxoꢀ
propyl)ꢀ3Hꢀimidazoleꢀ4ꢀcarboxamide (9c), Nꢀmethylꢀ3ꢀ(2ꢀoxoꢀ
propyl)ꢀ5ꢀ(3ꢀphenylꢀ2ꢀpropylꢀEꢀisothioureido)ꢀ3Hꢀimidazoleꢀ4ꢀ
carboxamide (9d), Nꢀpꢀtolylꢀ5ꢀ(2ꢀethylꢀ3ꢀphenylꢀEꢀisothioꢀ
ureido)ꢀ3ꢀ(2ꢀoxopropyl)ꢀ3Hꢀimidazoleꢀ4ꢀcarboxamide (9e), and
Nꢀpꢀtolylꢀ3ꢀ(2ꢀoxopropyl)ꢀ5ꢀ(3ꢀphenylꢀ2ꢀpropylꢀEꢀisothioꢀ
ureido)ꢀ3Hꢀimidazoleꢀ4ꢀcarboxamide (9f). Triethylamine (0.07 g,
0.76 mmol) and chloroacetone (0.07 g, 0.76 mmol) were added

2302
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 10, October, 2004
Eltsov et al.
to a solution of imidazolylisothiourea 8a—f (0.69 mmol) in 2 mL
of DMF. The reaction mixture was kept at 70 °C for 2 to 4 h and
diluted with ice water. The product was filtered off and recrysꢀ
tallized from aqueous ethanol.
References
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2ꢀEthylꢀEꢀ1ꢀ(6ꢀmethylꢀ8ꢀoxoꢀ7, 8ꢀdihydroimidꢀ
azo[1,5ꢀa]pyrazinꢀ1ꢀyl)ꢀ3ꢀphenylisothiourea (11a), Eꢀ1ꢀ(6ꢀmeꢀ
thylꢀ8ꢀoxoꢀ7,8ꢀdihydroimidazo[1,5ꢀa]pyrazinꢀ1ꢀyl)ꢀ3ꢀphenylꢀ2ꢀ
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imidazo[1,5ꢀa]pyrazinꢀ1ꢀyl)ꢀ2ꢀethylꢀ3ꢀphenylisothiourea (11c),
and Eꢀ1ꢀ(6,7ꢀdimethylꢀ8ꢀoxoꢀ7,8ꢀdihydroimidazo[1,5ꢀa]pyrazinꢀ
1ꢀyl)ꢀ3ꢀphenylꢀ2ꢀpropylisothiourea (11d). A solution of imidꢀ
azolylisothiourea 9a—d (0.76 mmol) in 5 mL of acetic acid
was refluxed for 30 min and concentrated. The residue was
crystallized from aqueous ethanol to give imidazopyrazinoꢀ
nes 11a—d.
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This work was financially supported by the Russian
Foundation for Basic Research (Project No. 98ꢀ03ꢀ
33044a) and the INTAS (Grant 97ꢀ0217).
Received December 8, 2000;
in revised form July 5, 2004