A new method for the synthesis of 5-amidinobarbiturates

Article abstract of DOI:10.1007/s11172-007-0253-3

The reactions of 5-[arylamino(methylthio)methylene]pyrimidine-2,4,6(1H,3H, 5H)-triones with different aliphatic and aromatic amines were studied. A series of 5-amidinobarbiturates was synthesized. A new and preparatively convenient method for their synthesis appropriate for the use in the combinatorial chemistry was developed.

Full text of DOI:10.1007/s11172-007-0253-3

Russian Chemical Bulletin, International Edition, Vol. 56, No. 8, pp. 1617—1623, August, 2007
1617
A new method for the synthesis of 5ꢀamidinobarbiturates
I. V. Paramonov, N. A. Belyaev, and V. A. Bakulevꢀ
Ural State Technical University,
19 ul. Mira, 620002 Ekaterinburg, Russian Federation.
Fax: +7 (343 2) 74 5483. Eꢀmail: bakulev@mail.ustu.ru
The reactions of 5ꢀ[arylamino(methylthio)methylene]pyrimidineꢀ2,4,6(1H,3H,5H )ꢀtriones
with different aliphatic and aromatic amines were studied. A series of 5ꢀamidinobarbiturates
was synthesized. A new and preparatively convenient method for their synthesis appropriate for
the use in the combinatorial chemistry was developed.
Key words: barbituric acids, thioimidates, thioamides, amidines.
Barbituric acid derivatives, such as Nembutal, Barꢀ
bital, and Benzobamil, are known drugs with soporific or
antispasmodic effect. Substances of this class manifest a
wide range of biological activity.1—4
differences in reactivity were found for barbituric acids in
the reactions with isothiocyanates, except for 1,3ꢀdiꢀ
methylbarbituric acid. For the latter we had to apply anꢀ
other order of reactant loading. The structures of syntheꢀ
sized thioamides 4 were confirmed by the data of the
1H NMR spectra and elemental analysis. In the second
step, thioamides 4 reacted with methyl iodide to form
methyl thioimidates 5 similarly to the process described8
for compounds 5 with the substituents R1 = R2 = H. The
structures of thioimidates 5 were confirmed by the presꢀ
ence of the signal from the SMe group at 2 ppm in the
1H NMR spectra of these compounds. Amidines 3 were
synthesized in 50—90% yields by the reactions of thioꢀ
imidates 5 with amines in a DMF solution. The reactions
of methyl thioimidates 5 with various types of amines
were studied. It was shown that the primary aliphatic
amines, benzylamines, tryptamines, and histamine react
smoothly with thioimidates 5 and form amidines 3 in high
yields according to the procedure developed. The reacꢀ
tions of compound 5 with aromatic amines occur someꢀ
what more slowly and require the use of larger aniline
excess. At the same time, this does not affect the yield of
the final compounds, and N,Nꢀdiarylamidines 3 were obꢀ
tained in high yields. Secondary amines are the least reacꢀ
tive compounds. For instance, the reactions of thioꢀ
imidates 5 with morpholine, dimethylamine, and piperiꢀ
dine occur very slowly, and we succeeded to isolate only
the starting compounds contaminated with resinꢀlike deꢀ
composition products of the amidines formed.
The data on barbituric acid derivatives 1 possessing
antitumor and immodulating activity were published.5—7
For the purpose of searching for new compounds maniꢀ
festing activity of these types, a series of barbituric acid
derivatives 2 with the amidine group in position 5 of the
pyrimidine cycle was synthesized by the reactions of barꢀ
bituric acids with carbodiimides.7 In spite of certain
achievements, the method developed is substantially reꢀ
stricted by a small arsenal of commercial carbodiimides
and provides only amidines with the same substituents at
the nitrogen atoms of the amidine group. It should be
mentioned that the reaction is very sensitive to air
moisture.
To develop a new, more general and preparatively
convenient method for the synthesis of 5ꢀamidinoꢀ
barbiturates 3, we synthesized thioamides 4, which furꢀ
ther transformed into thioimidates 5, and the latter were
involved in the reactions with aliphatic and aromatic
amines (Scheme 1).
Starting thioimidates 5 were obtained by the twoꢀstep
synthesis from barbituric acids 6. In the first step, pyriꢀ
midinetriones 6 were condensed with various aryl isoꢀ
thiocyanates using a modified procedure.8 No substantial
The structures of the synthesized amidines were conꢀ
firmed by the data of 1H NMR spectroscopy and elemenꢀ
tal analysis (Table 1). The existence of the double bond in
position 5 of the pyrimidine ring was proved as follows.
The spectra of all synthesized amidines 3 and intermediꢀ
ate compounds 4 and 5 contain no signal of the proton
at 3—4 ppm characteristic of 5,5ґꢀdisubstituted barbituꢀ
ric acids and exhibited two groups of protons of the
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1557—1563, August, 2007.
1066ꢀ5285/07/5608ꢀ1617 © 2007 Springer Science+Business Media, Inc.

1618
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 8, August, 2007
Paramonov et al.
Scheme 1
R1 = H (3a—l, 4a—h, 5a—h, 6a—e), cycloꢀC6H11 (3m,n, 4i, 5i, 6f), Me (3p,q,r, 4j,k, 5j,k, 6g)
R
2 = 4ꢀBrC6H4 (6a), 4ꢀMeC6H4 (6b), 4ꢀMeOC6H4 (6c), 2,4ꢀMe2C6H3 (6d), 2ꢀEtOC6H4 (6e), cycloꢀC6H11 (6f), Me (6g)
3
R2
R3
R4
3
R2
R3
R4
a
b
4ꢀBrC6H4
Ph
MeOC2H4
j
2ꢀEtOC6H4
Ph
4ꢀBrC6H4
3,5ꢀF2C6H3
k
2ꢀEtOC6H4
Ph
c
d
4ꢀMeC6H4
4ꢀMeC6H4
Ph
Ph
MeOC2H4
l
2ꢀEtOC6H4
Ph
Ph
4ꢀFC6H4CH2
m
cycloꢀC6H11
2ꢀCF3C6H4CH2
e
f
4ꢀMeOC6H4
4ꢀMeOC6H4
Ph
2ꢀClC6H4CH2
n
p
cycloꢀC6H11
Ph
Ph
4ꢀMeC6H4
Me
2ꢀClC6H4CH2
g
h
4ꢀMeOC6H4
4ꢀMeOC6H4
4ꢀMeC6H4
4ꢀMeC6H4
4ꢀCF3C6H4
4ꢀMeC6H4
q
r
Me
Me
2ꢀClC6H4
2ꢀClC6H4
4ꢀCF3C6H4
i
2,4ꢀMe2C6H3
4ꢀClC6H4
4, 5
R2
R3
4, 5
R2
R3
a
b
c
d
e
f
4ꢀBrC6H4
4ꢀBrC6H4
4ꢀBrC6H4
4ꢀMeC6H4
4ꢀMeOC6H4
4ꢀMeOC6H4
Ph
3,5ꢀF2C6H3
2ꢀClC6H4
Ph
g
h
i
j
k
2,4ꢀMe2C6H3
2ꢀEtOC6H4
cycloꢀC6H11
Me
4ꢀClC6H4
Ph
Ph
Ph
2ꢀClC6H4
Ph
Me
4ꢀMeC6H4

New method for synthesis of amidinobarbiturates
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 8, August, 2007
1619
NHꢀamidine group at 10—13 ppm. It should be menꢀ
tioned that the 1H NMR spectra of compounds 4f,h,j
contain downfield signals from the protons of the
atoms of the amide fragments, we have to admit that this
assumption is unsatisfactory. Moreover, a more probable
reason, in our opinion, is a higher basicity of the amide
fragment compared to the anilide fragments of barbituric
acids 6, resulting in the predominant binding of R3NH
with the most basic oxygen atom and the formation of one
isomer of thioamides 4 and thioimidates 5. Probably, upon
the formation of amidines the configuration of the
enamine fragment remains unchanged, which results in
the formation of one of possible isomers.
The method developed by us for the synthesis of
5ꢀamidinobarbituric acids 3 is general and appropriate for
the preparation of the synthesized compounds in large
amounts. Since the yield of the target products is high,
the procedures are universal and simple, and four centers
1
SH groups at 15—16 ppm. Thus, the H NMR spectral
data indicate the presence of the enamine fragment in the
structures of compounds 3—5. Based on the structures of
Nꢀmonosubstituted (R = H) pyrimidines 3, we could
expect the formation of a mixture of the cisꢀ and
transꢀisomers and the double set of signals in the 1H NMR
spectra of these compounds. However, the 1H NMR specꢀ
tra contain only one set of signals from protons. This
could be assigned to the easy rotation of the amidine
group due to the great contribution of the imino form of
compounds 3. Taking into account the presence of two
hydrogen bonds between the NH protons and oxygen
Table 1. Melting points, yields, and elemental analysis data for the synthesized compounds
Comꢀ
pound
Yield
(%)
M.p./°С
Found
Calculated
Empirical
formula
(%)
N
C
H
S
3a
3b
3c
3d
3e
3f
80
62
76
62
96
95
47
72
53
88
85
82
78
86
79
85
81
243—244
241—243
212—213
238—239
244—245
296—298
210—212
265—267
206—208
177—178
159—160
147—148
185—186
117—119
198—199
210—212
227—229
51.88
52.30
55.62
55.88
64.11
63.95
67.44
67.56
62.88
62.96
62.35
62.60
61.37
61.18
68.72
68.41
63.59
63.79
64.15
64.02
62.95
63.27
66.30
66.51
65.77
65.48
70.88
70.56
60.02
60.23
60.51
60.06
52.79
53.05
4.30
4.17
3.62
3.47
5.55
5.62
4.42
4.76
4.22
4.44
5.22
5.25
4.11
4.15
5.18
5.30
4.55
4.62
6.20
5.97
6.50
6.33
7.22
6.98
6.32
6.20
8.35
8.43
4.95
4.80
6.42
6.57
3.49
3.56
11.85
12.20
11.75
12.07
13.81
14.20
12.29
12.61
11.48
11.75
18.45
18.25
11.24
10.98
12.43
12.27
12.50
12.83
10.91
11.06
14.42
14.19
13.71
13.85
10.16
9.85
—
C20H19BrN4O4
C27H20BrF2N5O3
C21H22N4O4
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
C25H21FN4O3
C25H21ClN4O4
C24H24N6O4
3g
3h
3i
C26H21F3N4O4
C26H24N4O4
C29H25ClFN5O3
C27H30N4O6
3j
3k
3l
C26H31N5O5
C28H35N5O4
3m
3n
3p
3q
3r
C31H35F3N4O3
C33H47N5O3
12.27
12.47
14.46
14.05
15.20
15.23
12.41
12.37
C20H19ClN4O3
C23H30ClN5O3
C20H16ClF3N4O3
(to be continued)

1620
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 8, August, 2007
Paramonov et al.
Table 1 (continued)
Comꢀ
pound
Yield
(%)
M.p./°С
Found
Calculated
Empirical
formula
(%)
N
C
H
S
4a
4b
4c
4d
4e
4f
69
46
60
76
61
68
72
65
91
69
55
82
55
83
81
80
93
76
41
46
78
70
238—240
125—128
181—183
221—223
215—217
207—209
155—158
174—175
90—91
48.65
48.82
45.22
44.95
44.87
45.10
60.85
61.18
58.88
58.53
59.21
59.52
56.56
56.79
60.22
59.92
64.44
64.61
53.77
53.50
47.65
47.93
49.75
50.01
46.48
46.17
46.35
46.32
61.87
62.11
59.43
59.52
60.09
60.44
58.08
57.76
60.70
60.44
64.94
65.28
55.46
55.07
49.18
49.49
2.93
2.89
2.11
2.22
2.38
2.45
4.06
4.28
4.22
4.09
4.40
4.47
4.26
4.01
4.30
4.47
6.75
6.84
4.32
4.50
3.68
3.71
3.44
3.26
2.77
2.58
3.10
2.81
4.49
4.66
4.66
4.47
5.01
4.82
4.45
4.36
4.80
4.82
6.95
7.08
5.08
4.95
4.22
4.15
9.86
10.05
8.96
9.25
8.85
7.55
7.67
7.39
7.06
7.33
7.08
9.32
9.07
8.35
8.68
8.77
8.36
8.22
7.98
8.15
8.36
7.28
7.50
9.76
11.01
10.16
9.84
7.35
7.42
6.51
6.85
7.15
6.87
8.55
8.73
8.55
8.36
8.05
8.07
7.55
7.71
8.01
8.07
7.05
7.26
10.82
10.50
9.59
9.44
C17H12BrN3O3S
C17H10BrF2N3O3S
C17H11BrClN3O3S
C18H15N3O3S
9.28
11.97
11.89
11.44
11.38
11.44
10.96
10.23
10.46
11.31
10.96
9.75
C18H15N3O4S
C19H17N3O4S
4g
4h
4i
C19H16ClN3O3S
C19H17N3O4S
C23H29N3O3S
9.83
4j
155—156
177—178
267—269
242—244
242—244
243—244
214—215
221—223
156—158
204—205
152—154
147—148
200—201
14.13
14.42
13.13
12.90
9.88
9.72
9.29
8.97
9.33
C13H13N3O3S
4k
5a
5b
5c
5d
5e
5f
C13H12ClN3O3S
C18H14BrN3O3S
C18H12BrF2N3O3S
C18H13BrClN3O3S
C19H17N3O3S
9.00
11.29
11.44
11.35
10.96
10.44
10.57
10.50
10.10
11.00
10.57
9.81
C19H17N3O4S
C20H19N3O4S
5g
5h
5i
C20H18ClN3O3S
C20H19N3O4S
C24H31N3O3S
9.52
5j
14.03
13.76
12.21
12.37
C14H15N3O3S
5k
C14H14ClN3O3S
the internal standard. Chemical shifts were measured in the
δ scale. The reaction course and individual character of the
synthesized substances were monitored by TLC on Sorbfil Ufꢀ254
plates in a chloroform—ethanol (10 : 1) system. Melting points
were not corrected.
Starting barbituric acids 6a—g were purchased from
PubChem (National Center for Biotechnology Information,
National Library of Medicine, Building 38A Bethesda,
MD 20894, USA). The physicochemical characteristics and
of a molecule of compounds 3 can be modified, we recꢀ
ommend to use the developed method in the combinatoꢀ
rial chemistry.
Experimental
1
Н NMR spectra were recorded on a Bruker WMꢀ250 inꢀ
strument (250.13 MHz) in a DMSOꢀd6 solution using Me4Si as

New method for synthesis of amidinobarbiturates
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 8, August, 2007
1621
yields of the substances are given in Table 1. The characteristics
of the Н NMR spectra of the synthesized compounds are preꢀ
sented in Table 2.
5 ꢀ [ A m i n o ( m e r c a p t o ) m e t h y l e n e ] p y r i m i d i n e ꢀ
2,4,6(1H,3H,5H )ꢀtriones 5 (general procedure). Method A
(for 4a—i). The corresponding barbituric acid 6 (10 mmol) and
aryl isothiocyanate (10 mmol) were added to a solution of soꢀ
dium ethoxide prepared from sodium (10 mmol) and anhydrous
ethanol (40 mL). The mixture was refluxed for 5—10 h, cooled,
and kept for 16 h in a refrigerator. A precipitate of thioamide
sodium salt 4 was filtered off, washed with a minor amount of
alcohol, and dissolved in water. The solution was filtered, and
the filtrate was acidified with HCl to рН = 1—2. The precipitate
was filtered off, washed with water, and dried. If no precipitate
formed upon cooling, the solution was filtered with carbon, and
the filtrate was acidified with HCl to рН = 1—2. The precipitate
1
Table 2. Data for the 1Н NMR spectra of the synthesized compounds
Comꢀ
pound
δ (J/Hz)
4a
4b
7.31—7.38 (m, 3 H, СHAr); 7.42—7.48 (m, 4 H, СHAr); 7.68—7.72 (m, 2 H, СHAr);
12.75, 13.62 (both s, 1 H each, NH)
7.02 (t, 1 H, СHAr, J = 7.0); 7.11—7.22 (m, 4 H, СHAr); 7.66 (d, 2 H, СHAr, J = 7.0);
12.54, 13.58 (both s, 1 H each, NH)
4c
4d
4e
7.23—7.41 (m, 4 H, СHAr); 7.50—7.54 (m, 1 H, СHAr); 7.60—7.68 (m, 3 H, СHAr); 13.54 (s, 1 H, NH)
2.46 (s, 3 H, СH3); 7.08 (d, 2 H, СHAr, J = 8.0); 7.22—7.48 (m, 7 H, СHAr); 12.73, 13.80 (both s, 1 H each, NH)
3.69 (s, 3 H, СH3); 6.98, 7.11 (both d, 2 H each, СHAr, J = 8.8); 7.32—7.48 (m, 5 H, СHAr);
12.83, 13.85 (both s, 1 H each, NH)
4f
2.35, 3.81 (both s, 3 H each, СH3); 6.95—6.99 (m, 2 H, СHAr); 7.13—7.21 (m, 4 H, СHAr); 7.31 (d, 2 H,
СHAr, J = 8.2); 12.60, 13.64 (both s, 1 H each, NH); 15.79 (s, 1 H, SH)
2.13, 2.39 (both s, 3 H each, СH3); 6.97 (d, 1 H, СHAr, J = 8.0); 7.15 (t, 2 H, СHAr, J = 8.0); 7.38—7.49
(m, 4 H, СHAr); 12.65, 13.68 (both s, 1 H each, NH)
1.32 (t, 3 H, CH3, J = 7.0); 4.09 (q, 2 H, CH2, J = 7.0); 6.97—7.48 (m, 9 H, СHAr); 12.60, 13.69 (both s,
1 H each, NH); 17.44 (s, 1 H, SH)
4g
4h
4i
1.18—1.97 (m, 16 H, СH2); 2.32—2.45 (m, 4 H, СH2); 4.66—4.73 (m, 2 H, СH); 7.28—7.49 (m, 5 H, СHAr);
13.98 (s, 1 H, NH)
4j
4k
5a
3.32 (s, 6 H, СH3); 7.28—7.44 (m, 5 H, СHAr); 13.96 (s, 1 H, NH); 17.80 (s, 1 H, SH)
3.30 (s, 6 H, СH3); 7.41—7.46, 7.60—7.65 (both m, 2 H each, СHAr); 13.84 (s, 1 H, NH)
2.06 (s, 3 H, СH3); 7.22—7.25 (m, 2 H, СHAr); 7.31—7.39 (m, 3 H, СHAr); 7.47 (t, 2 H, СHAr, J = 8.0);
7.62—7.66 (m, 2 H, СHAr); 11.21, 13.41 (both s, 1 H each, NH)
5b
5c
5d
5e
5f
2.15 (s, 3 H, СH3); 6.93 (t, 1 H, СHAr, J = 7.0); 7.05—7.16 (m, 4 H, СHAr); 7.57 (d, 2 H, СHAr, J = 7.0);
11.24, 13.38 (both s, 1 H each, NH)
1.97 (s, 3 H, СH3); 7.26 (d, 2 H, СHAr, J = 8.4); 7.37—7.48 (m, 2 H, СHAr); 7.47 (d, 1 H, СHAr, J = 8.0);
7.63—7.66 (m, 3 H, СHAr); 11.35, 13.66 (both s, 1 H each, NH)
1.99, 2.38 (both s, 3 H each, СH3); 7.03 (d, 2 H, СHAr, J = 8.0); 7.19—7.45 (m, 7 H, СHAr);
11.06, 13.72 (both s, 1 H each, NH)
2.00, 3.80 (both s, 3 H each, СH3); 6.93, 7.07 (both d, 2 H each, СHAr, J = 8.8); 7.27—7.43 (m, 5 H, СHAr);
11.05, 13.73 (both s, 1 H each, NH)
2.04, 2.33, 3.78 (all s, 3 H each, СH3); 6.95—6.99 (m, 2 H, СHAr); 7.14 (d, 2 H, СHAr, J = 8.8); 7.24—7.29
(m, 4 H, СHAr); 11.12, 13.45 (both s, 1 H each, NH)
5g
5h
5i
2.04, 2.07, 2.34 (all s, 3 H each, СH3); 6.92 (d, 1 H, СHAr, J = 8.0); 7.05 (t, 2 H, СHAr, J = 8.0); 7.35—7.45
(m, 4 H, СHAr); 11.10, 13.57 (both s, 1 H each, NH)
1.29 (t, 3 H, CH3, J = 9.0); 2.02 (c, 3 H, CH3); 4.05 (q, 2 H, CH2, J = 9.0); 6.97—7.11 (m, 3 H, СHAr);
7.28—7.46 (m, 6 H, СHAr); 11.02, 13.65 (both s, 1 H each, NH)
1.15—1.85 (m, 16 H, СH2); 1.96 (s, 3 H, СH3); 2.26—2.40 (m, 4 H, СH2); 4.59—4.68 (m, 2 H, СH); 7.25—7.47
(m, 5 H, СHAr); 13.91 (s, 1 H, NH)
5j
5k
2.03, 3.16 (both s, 6 H each, СH3); 7.32—7.40 (m, 3 H, СHAr); 7.46—7.50 (m, 2 H, СHAr); 13.52 (s, 1 H, NH)
1.95 (s, 3 H, СH3); 3.19 (s, 6 H, СH3); 7.37—7.48 (m, 2 H, СHAr); 7.57 (d, 1 H, СHAr, J = 8.0); 7.65—7.67
(m, 1 H, СHAr); 13.75 (s, 1 H, NH)
3a
3b
2.87—2.9 (m, 2 H, СH2); 3.19 (s, 3 H, СH3); 3.3—3.38 (m, 2 H, СH2); 7.23—7.29 (m, 5 H, СHAr); 7.41—7.45
(t, 2 H, СHAr); 7.62—7.65 (m, 2 H, СHAr); 11.06, 11.12, 12.30 (all s, 1 H each, NH)
2.90 (t, 2 H, СH2, J = 6.0); 3.18 (d, 2 H, СH2, J = 6.0); 6.93 (m, 1 H, СHAr); 7.02—7.09 (m, 5 H, СHAr); 7.22
(d, 2 H, СHAr, J = 8.4); 7.32 and 7.38 (AA´BB´ system, 2 H, СHAr, J = 8.0); 7.63—7.65 (m, 2 H, СHAr);
10.85, 11.07, 11.19, 12.15 (all s, 1 H each, NH)
(to be continued)

1622
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 8, August, 2007
Paramonov et al.
Table 2 (continued)
Comꢀ
pound
δ (J/Hz)
3c
3d
3e
3f
2.34 (s, 3 H, СH3); 2.86—2.9 (m, 2 H, СH2); 3.19 (s, 3 H, СH3); 3.25—3.37 (m, 2 H, СH2); 7.10 (d, 2 H, СHAr
J = 8.4); 7.22—7.29 (m, 5 H, СHAr); 7.41—7.45 (t, 2 H, СHAr); 11.04, 11.11, 12.36 (all s, 1 H each, NH)
2.37 (s, 3 H, СH3); 3.98 (d, 2 H, СH2, J = 5.5); 6.98—7.43 (m, 13 H, СHAr); 10.93,
11.29, 12.48 (all s, 1 H each, NH)
3.79 (s, 3 H, СH3); 4.08 (d, 2 H, СH2, J = 5.5); 6.92 and 7.05 (AA´BB´ system, 4 H, СHAr, J = 8.7); 7.19—7.42
(m, 9 H, СHAr); 10.91, 11.29, 12.55 (all s, 1 H each, NH)
2.30 (s, 3 H, СH3); 2.60 (t, 2 H, СH2, J = 6.4); 2.99 (m, 2 H, СH2); 3.78 (s, 3 H, СH3); 6.69 (s, 1 H, СHimide);
6.95—6.98 (m, 2 H, СHAr); 7.11—7.15 (m, 4 H, СHAr); 7.22 (d, 2 H, СHAr, J = 8.0); 7.48 (d, 1 H,
СHimide, J = 1.2); 10.93, 11.00, 11.74, 12.25 (all s, 1 H each, NH)
3g
3h
3i
2.12, 3.81 (both s, 3 H each, СH3); 6.81 (s, 4 H, СHAr); 6.95 (d, 2 H, СHAr, J = 9.0); 7.09 (t, 4 H, СHAr, J = 9.2);
7.27 (d, 2 H, СHAr, J = 8.2); 11.16, 12.82, 12.89 (all s, 1 H each, NH)
2.14 (s, 6 H, СH3); 3.81 (s, 3 H, СH3); 6.73—6.82 (m, 8 H, СHAr); 6.94 and 7.08 (AA´BB´ system, 4 H, СHAr
J = 9.0); 11.04 (s, 1 H, NH); 12.70 (s, 2 H, NH)
,
2.04, 2.34 (both s, 3 H each, СH3); 2.83, 3.11 (both t, 2 H each, СH2, J = 6.8); 6.77—7.38 (m, 11 H, СHAr);
10.77, 10.90, 11.07, 12.32 (all s, 1 H each, NH)
3j
0.79—0.82 (m, 2 H, СH2); 1.19—1.22 (m, 5 H, СH2 + СH3); 1.33—1.38 (m, 1 H, СH); 1.50—1.53, 1.81—1.83
(both m, 2 H each, СH2); 2.0—2.04 (m, 1 H, СH); 2.60—2.64, 4.00—4.03 (both m, 2 H each, СH2); 6.98—7.45 (m,
9 H, СHAr); 11.01, 11.07, 12.0, 12.31 (all s, 1 H each, NH)
3k
3l
1.21 (t, 3 H, СH3, J = 7.0); 1.51—1.55 (m, 2 H, СH2); 2.12—2.19 (m, 6 H, СH2); 2.81—2.84 (m, 2 H, СH2);
3.46—3.48 (m, 4 H, СH2); 3.99—4.04 (m, 2 H, СH2); 6.95—7.45 (m, 9 H, СHAr); 10.91,
11.04, 12.30 (all s, 1 H each, NH)
0.55 (s, 6 H, СH3); 0.82—0.91 (m, 8 H, 2 СH3 + СH2); 1.21 (t, 3 H, СH3, J = 7.0); 1.60—1.64 (m, 2 H, СH2);
3.48—3.52 (m, 1 H, СH); 4.00—4.05 (m, 2 H, СH2); 6.95—7.47 (m, 9 H, СHAr); 10.87 (d, 1 H, NH J = 8.8);
11.06, 12.43 (both s, 1 H each, NH)
3m
3n
1.05—1.85 (m, 16 H, СH2); 2.25—2.40 (m, 4 H, СH2); 4.08 (d, 2 H, СH2, J = 5.5); 4.54—4.74 (m, 2 H, СH);
6.90—7.42 (m, 9 H, СHAr); 11.29, 12.55 (both s, 1 H each, NH)
1.09—1.82 (m, 30 H, СH2); 2.28—2.41 (m, 4 H, СH2); 2.60 (d, 2 H, СH2, J = 11.0); 2.90—3.04 (m, 2 H, СH2);
4.51—4.71 (m, 2 H, СH); 7.16—7.44 (m, 5 H, СHAr); 11.25, 12.67 (both s, 1 H each, NH)
3.16 (s, 6 H, СH3); 4.09 (d, 2 H, СH2, J = 5.5); 7.18—7.42 (m, 9 H, СHAr); 11.42, 12.67 (both s, 1 H each, NH)
1.09—1.82 (m, 14 H, СH2); 2.62 (d, 2 H, СH2, J = 11.0); 2.87—3.01 (m, 2 H, СH2); 3.21 (s, 6 H, СH3);
7.26—7.53 (m, 3 H, СHAr); 7.55 (m, 1 H, СHAr); 11.24, 12.37 (both s, 1 H each, NH)
3.28 (s, 6 H, СH3); 6.89—7.34 (m, 8 H, СHAr); 13.06, 13.11 (both s, 1 H each, NH)
3p
3q
3r
was filtered off, washed with water, dried, and crystalꢀ
lized from ethanol. (5Z )ꢀ5ꢀ[Anilino(mercapto)methylene]ꢀ1ꢀ
(4ꢀbromophenyl)pyrimidineꢀ2,4,6(1H,3H,5H )ꢀtrione (4a),
(5Z )ꢀ1ꢀ(4ꢀbromophenyl)ꢀ5ꢀ{[(3,5ꢀdifluorophenyl)amino](merꢀ
capto)methylene}pyrimidineꢀ2,4,6(1H,3H,5H )ꢀtrione (4b),
(5Z )ꢀ1ꢀ(4ꢀbromophenyl)ꢀ5ꢀ{[(2ꢀchlorophenyl)amino](merꢀ
capto)methylene}pyrimidineꢀ2,4,6(1H,3H,5H )ꢀtrione (4c),
(5Z )ꢀ5ꢀ[anilino(mercapto)methylene]ꢀ1ꢀ(4ꢀmethylphenyl)pyriꢀ
midineꢀ2,4,6(1H,3H,5H )ꢀtrione (4d), (5Z )ꢀ5ꢀ[anilino(merꢀ
capto)methylene]ꢀ1ꢀ(4ꢀmethoxyphenyl)pyrimidineꢀ
2,4,6(1H,3H,5H )ꢀtrione (4e), (5Z )ꢀ5ꢀ{mercapto[(4ꢀmethylꢀ
phenyl)amino]methylene}ꢀ1ꢀ(4ꢀmethoxyphenyl)pyrimidineꢀ
2,4,6(1H,3H,5H )ꢀtrione (4f), (5Z )ꢀ5ꢀ{[(4ꢀchlorophenyl)amiꢀ
no](mercapto)methylene}ꢀ1ꢀ(2,4ꢀdimethylphenyl)pyrimidineꢀ
2,4,6(1H,3H,5H )ꢀtrione (4g), (5Z )ꢀ5ꢀ[anilino(mercapto)meꢀ
thylene]ꢀ1ꢀ(2ꢀethoxyphenyl)pyrimidineꢀ2,4,6(1H,3H,5H )ꢀ
trione (4h), or 5ꢀ[anilino(mercapto)methylene]ꢀ1,3ꢀdicycloꢀ
hexylpyrimidineꢀ2,4,6(1H,3H,5H )ꢀtrione (4i) were obtained.
Method B (for 4j,k). A solution of sodium ethoxide prepared
from sodium (10 mmol) and anhydrous ethanol (40 mL) was
slowly (for 2 h) added to a boiling solution of dimethylbarbituric
acid (10 mmol) and phenyl or 2ꢀchlorophenyl isothiocyanate
(10 mmol) in anhydrous ethanol (50 mL). The mixture was
refluxed for 3 h and left to stay for 16 h in a refrigerator.
A precipitate of thioamide sodium salt 4 was filtered off, washed
with a minor amount of alcohol, and dissolved in water. The
solution was filtered, and the filtrate was acidified with HCl to
рН = 1—2. The precipitate was filtered off, washed with water,
and dried. 5ꢀ[Anilino(mercapto)methylene]ꢀ1,3ꢀdimethylpyriꢀ
midineꢀ2,4,6(1H,3H,5H )ꢀtrione (4j) and 5ꢀ{[(2ꢀchloropheꢀ
nyl)amino](mercapto)methylene}ꢀ1,3ꢀdimethylpyrimidineꢀ
2,4,6(1H,3H,5H )ꢀtrione (4k) were obtained.
5 ꢀ [ A m i n o ( m e t h y l t h i o ) m e t h y l e n e ] p y r i m i d i n e ꢀ
2,4,6(1H,3H,5H )ꢀtriones 5 (general procedure). Methyl iodide
(5.5 mmol) and triethylamine (5.5 mmol) were added to a soluꢀ
tion of thioamide 4 (5 mmol) in DMF (10 mL), and the mixture
was kept at ambient temperature for 1 day. The solution
was diluted with water (50 mL), and the precipitate was filꢀ
tered off, dried, and crystallized from ethanol. (5Z )ꢀ5ꢀ[aniꢀ
lino(methylthio)methylene]ꢀ1ꢀ(4ꢀbromophenyl)pyrimidineꢀ
2,4,6(1H,3H,5H )ꢀtrione (5a), (5Z )ꢀ1ꢀ(4ꢀbromophenyl)ꢀ5ꢀ
{[(3,5ꢀdifluorophenyl)amino](methylthio)methylene}pyrimiꢀ
dineꢀ2,4,6(1H,3H,5H )ꢀtrione (5b), (5Z )ꢀ1ꢀ(4ꢀbromophenyl)ꢀ
5ꢀ{[(2ꢀchlorophenyl)amino](methylthio)methylene}pyrimidineꢀ

New method for synthesis of amidinobarbiturates
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 8, August, 2007
1623
2,4,6(1H,3H,5H )ꢀtrione (5c), (5Z )ꢀ5ꢀ[anilino(methylthio)meꢀ
thylene]ꢀ1ꢀ(4ꢀmethylphenyl)pyrimidineꢀ2,4,6(1H,3H,5H )ꢀ
trione (5d), (5Z )ꢀ5ꢀ[anilino(methylthio)methylene]ꢀ1ꢀ(4ꢀ
methoxyphenyl)pyrimidineꢀ2,4,6(1H,3H,5H )ꢀtrione (5e),
(5Z )ꢀ5ꢀ{methylthio[(4ꢀmethylphenyl)amino]methylene}ꢀ1ꢀ
(4ꢀmethoxyphenyl)pyrimidineꢀ2,4,6(1H,3H,5H )ꢀtrione (5f),
(5Z )ꢀ5ꢀ{[(4ꢀchlorophenyl)amino](methylthio)methylene}ꢀ1ꢀ
(2,4ꢀdimethylphenyl)pyrimidineꢀ2,4,6(1H,3H,5H )ꢀtrione (5g),
(5Z )ꢀ5ꢀ[anilino(methylthio)methylene]ꢀ1ꢀ(2ꢀethoxyꢀ
phenyl)pyrimidineꢀ2,4,6(1H,3H,5H )ꢀtrione (5h), 5ꢀ[aniliꢀ
no(methylthio)methylene]ꢀ1,3ꢀdicyclohexylpyrimidineꢀ
2,4,6(1H,3H,5H )ꢀtrione (5i), 5ꢀ[anilino(methylthio)methylꢀ
ene]ꢀ1,3ꢀdimethylpyrimidineꢀ2,4,6(1H,3H,5H )ꢀtrione (5j), or
5ꢀ{[(2ꢀchlorophenyl)amino](methylthio)methylene}ꢀ1,3ꢀdiꢀ
methylpyrimidineꢀ2,4,6(1H,3H,5H )ꢀtrione (5k) were obtained.
(5Z )ꢀ5ꢀ[Arylamino(alkylamino)methylene]ꢀ and (5Z )ꢀ5ꢀ
[arylamino(methylene)]pyrimidineꢀ2,4,6(1H,3H,5H )ꢀtriones 3
(general procedure). Compound 5 (0.3 mmol) and the correꢀ
sponding amine (0.33 mmol) were added to DMF (1 mL), and
the mixture was boiled for 3 min, cooled to ambient temperaꢀ
ture, and diluted with water. The precipitate was filtered off
and crystallized from ethanol. (5E)ꢀ5ꢀ{Anilino[(2ꢀmethoxyꢀ
phenyl)amino]methylene}ꢀ1ꢀ(4ꢀbromophenyl)pyrimidineꢀ
2,4,6(1H,3H,5H )ꢀtrione (3a), (E)ꢀ5ꢀ((2ꢀ(1Hꢀindolꢀ3ꢀyl)ethylꢀ
amino)(3,5ꢀdifluorophenylamino)methylene)ꢀ1ꢀ(4ꢀbromopheꢀ
nyl)pyrimidineꢀ2,4,6(1H,3H,5H )ꢀtrione (3b), (5E)ꢀ5ꢀ{aniliꢀ
no[(2ꢀmethoxyphenylamino]methylene}ꢀ1ꢀ(4ꢀmethylpheꢀ
nyl)pyrimidineꢀ2,4,6(1H,3H,5H )ꢀtrione (3c), (5E)ꢀ5ꢀ{aniliꢀ
no[(4ꢀfluorobenzyl)amino]methylene}ꢀ1ꢀ(4ꢀmethylphenyl)pyriꢀ
midineꢀ2,4,6(1H,3H,5H )ꢀtrione (3d), (Z )ꢀ5ꢀ[(2ꢀchlorobenzylꢀ
amino)(pꢀanilino)methylene]ꢀ1ꢀ(4ꢀmethoxyphenyl)pyrimidineꢀ
2,4,6(1H,3H,5H )ꢀtrione (3e), (Z )ꢀ5ꢀimidazole{[2ꢀ(1Hꢀimidꢀ
azolꢀ5ꢀyl)ethylamino](pꢀtoluidino)methylene}ꢀ1ꢀ(4ꢀmethoxyꢀ
phenyl)pyrimidineꢀ2,4,6(1H,3H,5H )ꢀtrione (3f), (E)ꢀ5ꢀ{[4ꢀ(triꢀ
fluoromethyl)phenylamino](pꢀtoluidino)methylene}ꢀ1ꢀ
(4ꢀmethoxyphenyl)pyrimidineꢀ2,4,6(1H,3H,5H )ꢀtrione (3g),
5ꢀ[bis(pꢀtoluidino)methylene]ꢀ1ꢀ(4ꢀmethoxyphenyl)pyrimiꢀ
dineꢀ2,4,6(1H,3H,5H )ꢀtrione (3h), (Z )ꢀ5ꢀ{[2ꢀ(5ꢀfluoroꢀ1Hꢀ
indolꢀ3ꢀyl)ethylamino](4ꢀchlorophenylamino)methylene}ꢀ1ꢀ
(2,4ꢀdimethylphenyl)pyrimidineꢀ2,4,6(1H,3H,5H )ꢀtrione (3i),
4ꢀ[({anilino[1ꢀ(2ꢀethoxyphenyl)ꢀ2,4,6ꢀtrioxotetrahydroꢀ5(2H )ꢀ
pyrimidinylidene]methyl}amino)methyl]cyclohexanecarboxylic
acid (3j), 5ꢀ((Z )ꢀanilino{[3ꢀ(4ꢀmorpholinyl)propyl]amino}meꢀ
thylidene)ꢀ1ꢀ(2ꢀethoxyphenyl)ꢀ2,4,6(1H,3H )ꢀpyrimidinetrione
(3k), 5ꢀ{(Z )ꢀanilino[(2,2,6,6ꢀtetramethylꢀ4ꢀpiperidinyl)amiꢀ
no]methylene}ꢀ1ꢀ(2ꢀethoxyphenyl)ꢀ2,4,6(1H,3H )ꢀpyrimidineꢀ
trione (3l), 5ꢀ(anilino{[2ꢀ(trifluoromethyl)benzyl]amino{meꢀ
thylene)ꢀ1,3ꢀdicyclohexylꢀ2,4,6(1H,3H,5H )ꢀpyrimidinetrione
(3m), 5ꢀ{anilino[(octahydroꢀ2Hꢀquinolizinꢀ1ꢀylmethyl)amiꢀ
no]methylene}ꢀ1,3ꢀdicyclohexylꢀ2,4,6(1H,3H,5H )ꢀpyrimidineꢀ
trione (3n), 5ꢀ{anilino[(2ꢀchlorobenzyl)amino]methylene}ꢀ1,3ꢀ
dimethylꢀ2,4,6(1H,3H,5H )ꢀpyrimidinetrione (3p), 5ꢀ{(2ꢀchloꢀ
roanilino)[(octahydroꢀ2Hꢀquinolizinꢀ1ꢀylmethyl)amino]meꢀ
thylene}ꢀ1,3ꢀdimethylꢀ2,4,6(1H,3H,5H )pyrimidinetrione (3q),
or 5ꢀ{(2ꢀchloroanilino)[4ꢀ(trifluoromethyl)anilino]methylene}ꢀ
1,3ꢀdimethylꢀ2,4,6(1H,3H,5H )ꢀpyrimidinetrione (3r) were obꢀ
tained.
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 04ꢀ03ꢀ
32926a).
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Received October 20, 2006;
in revised form May 8, 2007