Investigation of nitrogen- and sulfur-containing heterocycles. 53. Reactions of 5-amino-6-mercapto-pyrimidines with derivatives of p-chloronitrobenzene. Synthesis of a new heterocyclic system - Pyrimido [4,5-b]-1,4-benzothiazepine

Article abstract of DOI:10.1023/A:1017531903175

A series of pyrimidyl aryl sulfides was obtained from the reaction of 5-amino-6-mercaptopyrimidines with derivatives of p-chloronitrobenzene containing carbonyl functional groups. The properties of these sulfides and methods of their cyclization into deri

Full text of DOI:10.1023/A:1017531903175

Chemistry of Heterocyclic Compounds, Vol. 37, No. 2, 2001
INVESTIGATION OF NITROGEN-
AND SULFUR-CONTAINING HETEROCYCLES.
53*. REACTIONS OF 5-AMINO-6-MERCAPTO-
PYRIMIDINES WITH DERIVATIVES OF
p
-CHLORONITROBENZENE. SYNTHESIS
OF A NEW HETEROCYCLIC SYSTEM –
b
PYRIMIDO[4,5- ]-1,4-BENZOTHIAZEPINE
T. S. Safonova1, M. P. Nemeryuk1, N. A. Grineva1, M. A. Keremov2,
and M. M. Likhovidova1
A series of pyrimidyl aryl sulfides was obtained from the reaction of 5-amino-6-mercaptopyrimidines
with derivatives of p-chloronitrobenzene containing carbonyl functional groups. The properties of these
sulfides and methods of their cyclization into derivatives of a new tricylic system, pyrimido[4,5-b]-1,4-
benzothiazepine, were studied.
Keywords: aminomercaptopyrimidines, pyrimido[4,5-b]-1,4-benzothiazepines, pyrimidylarylamines,
pyrimidyl aryl sulfides, Smiles rearrangement.
In a continuation of our work to discover biologically active substances among 1,4-thiazine and
1,4-thiazepine bi- and tricyclic systems [1-4] we undertook the synthesis of derivatives of the previously
unknown heterocyclic system, pyrimido[4,5-b]-1,4-benzothiazepine. In this connection the reactions of 5-amino-
6-mercaptopyrimidines 1a-e with derivatives of p-chloronitrobenzene 2a-e were studied. It was observed that
the primary products of the reactions of 4-methoxy- and 4-dimethylamino-5-amino-6-mercaptopyrimidines 1a,b
with 2-chloro-1-methoxycarbonyl-5-nitrobenzene 2a in ethanol at 60-65°C in the presence of equimolar amount
of alkali were pyrimidyl aryl sulfides 3a,b. The IR spectra of these compounds contain NH2 group absorption
bands in the 3380-3480 cm-1 region and ester carbonyl group absorptions at 1725 cm-1, which are in agreement
with their structures.
_______
* For paper 52 see [1].
____________________________________________________________________________________________
1
Center for the Chemistry of Medicinals, All-Russian Chemical-pharmaceutical Science Research
2
Institute, Moscow 119815, Russia. Dagestan State University, Makhachkala 367010, Russia. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 2, 270-275, February, 2001. Original article submitted March 30,
1999.
0009-3122/01/3702-0245$25.00©2001 Plenum Publishing Corporation
245

R
N
R
MeOOC
MeOOC
Cl
NO2
NO2
NH2
SH
NH2
N
N
+
for 1a,b
S
N
2a
3a,b
1a–c
for 1c
O
C
D
R
N
H
N
NO2
N
S
4a–c
1a, 3a, 4a R = OMe; 1b, 3b, 4b R = NMe2; 1c, 4c R = NHMe
Heating sulfides 3a,b with an excess of alkali at 60-65°C led to closure of the thiazepine ring to form
4-methoxy- and 4-dimethylamino-8-nitro-6-oxo-5,6-dihydropyrimido[4,5-b]-1,4-benzothiazepines 4a,b.
When 5-amino-4-methylamino-6-mercaptopyrimidine (1c) reacted with compound 2a by boiling in
ethanol in the presence of alkali for 5 h the final reaction product – pyrimidobenzothiazepine 4a – was formed
without isolation of the intermediate pyrimidyl aryl sulfide and this is more suitable for synthetic purposes. The
structures of pyrimidobenzothiazepines 4a-c were confirmed by the presence of amide NH and CO group
absorption bands in their IR spectra at 3200-3190 and 1650-1665 cm-1 respectively.
Reactions of 5-amino-6-mercaptopyrimidines 1a,b,d with 2-chloro-1-cyano-5-nitrobenzene (2b) in
ethanol in the presence of alkali at 60-65°C gave sulfides 3c-e. These when boiled with sodium methoxide in
methanol underwent the Smiles rearrangement to give pyrimidylarylamines 5a-c. These compounds, unlike the
sulfides 3c-e, dissolve in aqueous alkali solutions and their IR spectra contain secondary amino group
absorption bands in the 3310-3320 cm-1 region.
NO2
NC
1a,b,d
+
Cl
2b
R
R
N
H
NC
NH2
N
NO2
N
N
NO2
N
S
NC
SH
5a–c
3c–e
1a,3c,5aR=OMe;1b,3d,5bR=NMe;1d,3e,5cR=NH2
2
The analogous reaction of compounds 1a-d with 6-chloro-5-cyano-2,4-dimethylpyridine (2c) gave either
pyrimidylpyridylamines 5d,e or sulfides 3f,g depending on the nature of substituent at C(4) in the pyrimidine ring.
R
Me
H
N
Me
N
NC
Cl
N
+
1a,b
SH
5d,e
Me
N
NC
Me
N
2c
Me
R
N
NH2
NC
N
1c,d
2c
+
S
Me
N
3f,g
1a,5dR=OMe;1b,5eR=NMe;1c,3fR=NHMe;1d,3gR=NH2
2
246

Pyrimidobenzothiazepines 4d-h are readily formed by the reaction 5-amino-6-mercaptopyrimidines 1a-d
and 5-amino-6-mercapto-1,3-dimethyluracil (1e) with 2-chloro-1-formyl-5-nitrobenzene (2d) in ethanolic alkali
solution. Their structures were confirmed by the presence of molecular ion peaks in their mass spectra and
signals for the azomethine proton at 8.64-9.67 ppm in their 1H NMR spectra.
R
H
C
H
C
O
NO2
N
NO2
N
1a-d
+
S
N
Cl
4d-g
2d
O
O
H
Me
C
Me
O
N
NH2
NO2
N
N
2d
+
S
O
N
N
SH
Me
Me
4h
1e
1a,4dR=OMe;1b,4eR=NMe;1c,4fR=NHMe;1d,4gR=NH2
2
Reactions of 5-amino-6-mercaptopyrimidines 1a,b with 1-acetyl-2-chloro-5-nitrobenzene (2e) gave
sulfides 3h,i. Attempts to cyclize sulfide 3h with either basic or acidic reagents were unsuccessful, whereas
sulfide 3i readily formed the pyrimidobenzothiazepine 4i on heating with ethanolic solution of hydrogen
chloride or phosphorus oxychloride.
The structures of sulfides 3h,i and the tricycle 4i were confirmed by the presence of peaks of the
corresponding molecular ions in their mass spectra. The IR spectra of compounds 3h,i contain absorption bands
for the NH2 and CO groups at 3340, 3430, and 1680 cm-1 respectively, while the IR spectrum of the tricycle 4i
contains C=C and C=N absorption bands at 1600 and 1620 cm-1.
O
C
O
C
R
N
NH2
Me
NO2
Me
NO2
N
1a,b
+
S
3h,i
Cl
2e
from
3i
Me
R
N
C
N
N
S
4i
3hR=OMe;3i,4iR=NMe
2
Sulfide 3i underwent the Smiles rearrangement on boiling in ethanol to give pyrimidylarylamine 5f.
Sulfide 3h did not undergo a similar rearrangement.
247

O
C
NMe2
NMe2
NH2
H
N
NO2
Me
NO2
N
N
∆
3i
S
3j
N
N
SH Me
C
O
N
C
R
OMe
5f
NH2
Me
N
3h
S
N
3k,l
3kR=OH;3lR=NH2
Compounds 3h and 3i gave characteristic derivatives at the carbonyl group (e.g., oximes 3j,k and
hydrazone 3l). Their structures were confirmed by the presence of the corresponding molecular ions in their
mass spectra.
TABLE 1. Characteristics of the Compounds Synthesized
Found, %
mp, °С
(crystalli-
zation
——————
IR spectra,
Com-
Empirical
Yield,
%
Calculated, %
ν, см-1
pound formula
C
3
H
N
S
6
solvent)
1
2
4
5
7
8
9
C13H12N4O5S 46.60
46.50
3.66
3.58
16.54
16.65
9.80
9.53
189-192
1725, 3380,
3480
54
3a
(methanol)
C14H15N5O4S 48.08
4.37
20.16
9.29
144-146
1725, 3280,
47
69
76
82
3b
3c
3d
3e
48.14
4.29
20.05
9.17
(methanol)
3370
C12H9N5O3S
47.33
47.52
2.80
2.97
23.36 10.49
23.10 10.56
147-150
2200, 3260,
3360
(methanol)
C13H12N6O2S 49.15
3.67
26.87 10.19
185-187
2217, 3270,
49.36
3.76
26.58 10.12
(methanol)
3380
C11H8N6O2S
C13H14N6S
C12H12N6S
45.89
45.83
2.74
2.77
29.34 10.94
29.16 11.11
228-229
2219, 3285,
(H2O–DMF, 3375
1 : 3)
54.30
54.54
4.84
4.89
29.42
29.37
—
305-307
2216, 3270,
78
96
3f
(dec.)
3390
(DMF)
52.81
52.94
4.33
4.41
31.14 11.63
30.88 11.76
300
2218, 3275,
3g
(H2O–DMF, 3385
1 : 3)
C13H12N4O4S 48.34
48.75
3.71
3.75
17.83
9.99
184-186
1680, 3370,
54
40
95
95
46
3h
3i
17.50 10.00
(ethanol)
3470
C14H15N5O3S 50.41
4.43
21.21
21.02
9.68
9.61
148-149
1680, 3340,
50.45
4.50
3430
C14H16N6O3S 47.98
48.26
4.63
4.63
24.25
—
—
—
183-185
(ethanol)
3170, 3340,
3500
3j
3k
3l
24.13
C13H13N5O4S 46.37
3.85
20.90
20.89
186-188
3200, 3320,
46.56
3.91
(ethanol)
3455
C13H14N6O3S 46.45
46.70
4.06
4.19
25.26
185-187
(ethyl
1625, 3190,
3410
25.14
acetate)
C12H8N4O4S
47.30
47.37
2.65
2.63
18.44
18.42
—
265-267
(H2O–DMF,
1 : 1)
1665, 3200
62
4a
248

TABLE 1 (continued)
1
2
3
4
5
6
7
8
9
C13H11N5O3S 49.32
49.21
3.53
3.47
21.95 10.18
22.08 10.09
280-282
(H2O–DMF,
1 : 1)
1660, 3200
71
4b
C12H9N5O3S
C12H8N4O3S
47.48
47.52
2.99
2.97
23.34 10.86
300
1650, 3190,
3420
87
4c
23.40
10.56
(ethanol)
50.00
2.74
19.25 11.31
270-271
—
—
—
—
76
79
94
93
4d
4e
4f
49.99
2.79
19.43 11.12
(DMF)
C13H11N5O2S 51.65
51.81
C12H9N5O2S
4.02
3.68
23.17 10.57
23.24 10.64
229-231
(ethanol)
50.11
3.31
24.43 11.44
235-237
50.17
3.13
24.39 11.14
(ethanol)
C11H7N5O2S
48.55
48.34
2.57
2.58
3.16
3.16
25.89 11.70
25.63 11.73
17.45 10.22
17.60 10.07
257-259
(DMF)
4g
C13H10N4O4S 49.15
49.05
242-243
(H2O–DMF,
1 : 1)
—
70
4h
C14H13N5O2S 53.19
53.33
4.18
4.13
22.43
22.22
—
198-199
1600, 1620
2210, 3310
2205, 3320
84
90
4i
(ethanol)
C12H9N5O3S
47.33
47.57
3.00
2.97
23.10 10.46
23.10 10.56
232-234
(H2O)
5a
C13H12N6O2S 49.53
4.01
26.78 10.34
214-216
89
80
77
71
80
5b
5c
5d
5e
5f
49.36
3.76
26.58 10.12
(methanol)
C11H8N6O2S
C13H13N5OS
C14H16N6S
45.88
45.83
3.00
2.77
29.08 11.09
29.16 11.11
252-254
2218, 3210,
3320
(ethanol)
54.34
4.27
24.61 10.82
228-230
(ethanol)
2220, 3340
2225, 3380
1660, 3200
54.35
4.52
24.39 11.18
56.11
56.00
5.23
5.37
28.24 10.84
28.00 10.66
212-213
(ethanol)
C14H15N5O3S 50.59
4.62
20.95
—
228-230
(ethanol)
50.50
4.50
21.02
EXPERIMENTAL
1
IR spectra of nujol mulls were recorded with a Perkin Elmer 457 spectrometer. H NMR spectra of
DMSO-d6 solutions with TMS as internal standard were recorded with a Varian XL-200 apparatus. Mass
spectra were recorded with MX-1303 mass spectrometer. The course of reactions and the purity of products
were monitored by TLC on Silufol UV-254 plates with 5:5:1.5 benzene–ethyl acetate–ethanol as eluent. Spots
were visualized in UV light.
Elemental analyses and physicochemical characteristics of the compounds obtained are given in Table 1.
5-Amino-4-methoxy-6-(2-methoxycarbonyl-4-nitrophenyl)thiopyrimidine
(3a).
Solution
of
2-chloro-1-methoxycarbonyl-5-nitrobenzene 2a (1.08 g, 5 mmol) in methanol (25 ml) was added to solution of
5-amino-6-mercapto-4-methoxypyrimidine 1a (0.79 g, 5 mmol) and sodium hydroxide (0.2 g, 5 mmol) in
methanol (30 ml). The mixture was boiled for 3 h with stirring, cooled, the precipitate filtered off and dried to
give compound 3a (1.8 g). Compounds 3b-i were prepared analogously with the following boiling times: for
3c-e 1 h, for 3f 8 h, for 3g 20 h, and for 3h,i 2 h.
Oxime of 6-(2-Acetyl-4-nitrophenyl)-5-amino-4-methoxythiopyrimidine (3l). Solution of
hydroxylamine hydrochloride (0.2 g, 2.9 mmol) in water (15 ml) and sodium acetate (0.24 g) were added to
solution of sulfide 3i (0.5 g, 1.56 mmol) in ethanol (30 ml). The mixture was boiled for 5 h, the solution was
evaporated to dryness in vacuum, water (1 ml) was added to the residue which was then filtered, washed with
water, and dried to give compound 3l (0.5 g). Oxime 3k was prepared analogously.
249

Hydrazone of 6-(2-Acetyl-4-nitrophenyl)-5-amino-4-methoxythiopyrimidine (3m). Solution of
sulfide 3h (0.5 g, 1.55 mmol) and hydrazine hydrate (2 ml) in ethanol (10 ml) was boiled for 1.5 h, cooled, and
the precipitate was filtered off to give compound 3m (0.24 g).
b
Mixture of sodium
4-Methoxy-8-nitro-6-oxo-5,6-dihydropyrimido[4,5- ]-1,4-benzothiazepine (4a).
hydroxide (0.1 g, 2.5 mmol) and thioether 3a (0.64 g, 1.9 mmol) in methanol (20 ml) was boiled for 4 h and then
evaporated to dryness in vacuum. Water (10 ml) was added to the residue, the solution was acidified to pH 5-6
with 10% HCl, the precipitate was filtered off, washed with water and dried to give compound 4a (0.36 g).
Benzothiazepine 4b was prepared analogously.
b
Solution of 2-chloro-
4-Methylamino-6-oxo-5,6-dihydropyrimido[4,5- ]-1,4-benzothiazepine (4c).
1-methoxycarbonyl-5-nitrobenzene 2a (1.08 g, 5 mmol) in methanol (20 ml) was added to solution of 5-amino-
6-mercapto-4-methylaminopyrimidine 1c (0.78 g, 5 mmol) and sodium hydroxide (0.4 g, 10 mmol) in methanol
(30 ml). The mixture was heated at 60-63°C for 5 h, then methanol was evaporated in vacuum, water (10 ml)
was added to the residue, the solution was acidified to pH 5-6 with 10% HCl, the precipitate was filtered off,
washed with water, and dried to give compound 4c (1.30 g).
b
2-Chloro-1-formyl-5-nitrobenzene
2b
4-Methoxy-8-nitropyrimido[4,5- ]-1,4-benzothiazine (4d).
(0.56 g, 3 mmol) was added to solution of 5-amino-6-mercapto-4-methoxypyrimidine 1a (0.47 g, 3 mmol) in
methanol (30 ml) containing sodium hydroxide (0.2 g, 5 mmol) at 60-65°C. The mixture was boiled for 2 h with
stirring, cooled, the precipitate filtered off and dried to give compound 4d (0.6 g). Pyrimidobenzothiazepines
4e-h were prepared analogously.
b
Phosphorus oxychloride
4-Dimethylamino-6-methyl-8-nitropyrimido[4,5- ]-1,4-benzothiazine (4i).
(15 ml) was added to sulfide 3i (1 g, 3 mmol) and the mixture was kept at 20°C for 4 h. The reaction mixture
was poured onto ice and neutralized with aqueous ammonia. The precipitate was filtered off, washed with water,
and dried to give compound 4i (0.8 g). M+ 315.
6-Mercapto-4-methoxy-5-(2-cyano-4-nitrophenyl)aminopyrimidine (5a). Solution of sodium
methoxide in methanol (2.3 ml, 4%) was added at 60-65°C to solution of sulfide 3a (0.3 g, 10 mmol) in
methanol (16 ml). The reaction mixture was boiled for 1 h, evaporated to dryness in vacuum, and the residue
acidified to pH 6-7 with 10% HCl. The precipitate was filtered off, washed with ether, then water, and dried to
give compound 5a (0.24 g). Pyrimidylarylamines 5b and 5c were prepared analogously.
5-(3-Cyano-4,6-dimethylpyridyl-2)amino-6-mercapto-4-methoxypyrimidine (5d). Mixture of
compound 1a (0.78 g, 0.05 mol) and 2-chloro-3-cyano-4,5-dimethylpyridine 2c (0.83 g, 0.05 mol) in ethanol
(35 ml) was boiled for 8 h. The reaction mixture was cooled, the precipitate was filtered off, and dried to give
compound 5d (1.1 g). Compound 5e was made analogously.
4-Dimethylamino-6-mercapto-5-(2-acetyl-4-nitrophenyl)aminopyrimidine (5f).
Suspension of
sulfide 3i (0.92 g, 25 mmol) in ethanol (30 ml) was boiled for 40 h, cooled, the precipitate filtered off, and dried
to give compound 5f (0.64 g).
REFERENCES
1.
2.
T. S. Safonova, A. F. Keremov, and Yu. A. Ershova, Khim.-farm. Zh., 33, No. 1, 6 (1999).
T. S. Safonova, Targeted Research for New Antitumor and Antiviral Preparations [in Russian], Zinatne,
Riga (1978), p. 51.
T. S. Safonova, A. F. Keremov, and Yu. A Ershova, Khim.-farm. Zh., 32, No. 12, 11 (1998).
A. F. Keremov, M. P. Nemeryuk, O. L. Aparnikova, and T. S. Safonova, Khim. Geterotsikl. Soedin.,
1332 (1997).
3.
4.
250