Oxidative cyclocondensation of cyclic thio(seleno)ureas. 4. Electronic effects of the substituents and the medium

Article abstract of DOI:10.1007/s10593-006-0123-1

We have studied the electronic effect of substituents, steric factors, the medium, and the nature of the oxidizing agent on oxidative cyclocondensation of 2-thioxo-4-quinazolone and its substituted derivatives. We have found that electron-donor substituents promote the reaction while electronacceptor substituents inhibit the reaction. 2006 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10593-006-0123-1

Chemistry of Heterocyclic Compounds, Vol. 42, No. 4, 2006
OXIDATIVE CYCLOCONDENSATION
OF CYCLIC THIO(SELENO)UREAS.
4*. ELECTRONIC EFFECTS OF THE
SUBSTITUENTS AND THE MEDIUM
N. I. Mukarramov, B. A. Urakov, and Kh. M. Shakhidoyatov
We have studied the electronic effect of substituents, steric factors, the medium, and the nature of the
oxidizing agent on oxidative cyclocondensation of 2-thioxo-4-quinazolone and its substituted
derivatives. We have found that electron-donor substituents promote the reaction while electron-
acceptor substituents inhibit the reaction.
Keywords: 8H,15H-1,2,4-thiadiazolo[3,2-b:5,4-b']diquinazoline-8,15-dione, 2-thioxo-4-quinazolone,
quinazoline-2,4-dione, oxidative cyclocondensation, electronic substituent effects.
A rather large number of methods are known for obtaining 1,2,4-thia(seleno)diazoles from aliphatic
thio(seleno)amides [2-5], thioureas [6-9], thiocyanates and their derivatives [10, 11], amidines, amidoximes and
amidinothioureas [12-14], isothioureas [15], thiobiurets and thioguanidines [2, 16], thiatriazoles, dithiazoles,
oxazarines and heterocumulenes [17-21]. The simplest and most accessible method has proven to be the one
based on oxidation of thioamides and thioureas. Synthesis from amidino derivatives can be considered as an
intermediate step in obtaining them from thioureas and thioamides. The mechanism for the formation of
1
,2,4-thia(seleno)diazoles from thioamides and thioureas has not yet been studied in detail. The effect of various
factors on the course of the reaction also has not been studied (electronic effects of substituents, steric factors,
temperature, the nature of the solvent, the oxidizing agent, etc.). These reactions have not been generally studied
for cyclic thioureas. As far as 1,2,4-selenodiazoles are concerned, only their synthesis from selenobenzamides
[
22, 23] and amidines [11] has been described. Only a few derivatives in this class of compounds have been
synthesized.
Cyclic thio(seleno)ureas are a huge class of heterocyclic compounds. Pyrimidinones (the cyclic analogs
of thio(seleno)ureas) condensed with benzene, thiophene, and pyridine rings are of considerable interest for
theoretical organic chemistry, in connection with their existence in various tautomeric forms.
A large number of derivatives of these compounds have been synthesized so far. They include
substances having pesticidal and also other types of physiological activity.
_
*
_
______
For Communication 3, see [1].
_________________________________________________________________________________________
Academician S. Yu. Yunusov Institute of Plant Chemistry, Academy of Sciences of the Republic of
Uzbekistan, Tashkent 700170; e-mail: shakhi@icps.org.uz. Translated from Khimiya Geterotsiklicheskikh
Soedinenii, No. 4, pp. 616-622, April, 2006. Original article submitted December 1, 2003; revised October 27,
2
005.
5
40
0009-3122/06/4204-0540©2006 Springer Science+Business Media, Inc.

Most preparations in this series are used in agriculture and medicine. Despite the huge amount of data
accumulated and the appearance of new information from studying their reactivity, no literature data are
available on the reactions of oxidative cyclocondensation of cyclic thioureas and their analogs.
However, synthesis of polynuclear condensed derivatives of 1,2,4-thia(seleno)diazoles based on simple
cyclic thio(seleno)ureas is of great theoretical and practical interest. So it is important to study our recently
discovered novel reaction of symmetric and asymmetric oxidative cyclocondensation of cyclic thio(seleno)ureas
[24] and to search for biologically active compounds among condensed 1,2,4-thiadiazoles.
Earlier while studying the synthesis and reactivity of heterocyclic systems containing various hetero
atoms in the exocyclic position (2-oxo-, -thioxo, -selenoxo-, aminopyrimidines, thieno[2,3-d]pyrimidines,
quinazolines and their substituted derivatives), we observed that 2-thioxo-4-quinazolone (1a) in DMSO in the
presence of P O forms 8H,15H-1,2,4-thiadiazolo[3,2-b:5,4-b']diquinazoline-8,15-dione (2a) [24], i.e., undergo
2
5
oxidative cyclocondensation.
O
O
N
O
N
O
NH
N
NH
3
+
N
N
H
S
S
N
H
O
3
a
1
a
2a
With the aim of studying the effect of the nature of the oxidizing agent and the solvent, in the reaction of
oxidative cyclocondensation we used other solvents and different oxidizing agents besides DMSO and P O .
2
5
Carrying out the reaction in dry DMSO in the presence of P O for 1 h leads to formation of compound 2a in
2
5
3
0% yield (Table 1). Increasing the reaction time up to 10 h increases the product yield up to 60%, but along
with that we observe formation of 2-oxo-4-quinazolone (quinazoline-2,4-dione) (3a): the oxidation product of
the starting compound 1a (8%).
TABLE 1. Effect of the Nature of the Solvent and the Condensing Agent on
Oxidative Cyclocondensation of 2-Thioxo-4-quinazolone
Reaction conditions
Solvent + oxidizing agent
Yield, %
Time, h
2a
3a
DMSO
0
30
50
55
58
60
0
0
DMSO + Р
DMSO + Р
DMSO + Р
DMSO + Р
DMSO + Р
2
2
2
2
2
О
5
1
0
О
5
2
4
0
О
5
Traces
О
5
6
5
О
5
10
8
DMF + Р
DMF + Р
2
О
О
5
2
0
2
5
6
0
0
Dioxane + Р
Dioxane + Р
2
О
О
5
2
6
0
0
0
0
2
5
DMSO + H
DMSO + H
DMSO + H
2
2
2
SO
SO
SO
4
4
4
1
20
66
70
0
0
2
6
7
10
DMF + H
Dioxane + H
Abs. methanol. + I
Abs. methanol. + I
Abs. methanol. + I
2
SO
4
6
50
2
SO
4
6
0
Traces
2
5 min
10 min
20 min
45
50
58
0
0
0
2
2
5
41

The reactions do not occur in DMF, dioxane, or in alcohol in the absence or in the presence of P
2 5
O .
Cyclocondensation does not occur in these solvents even in the presence of concentrated H SO . In DMSO,
2
4
when we replace P O by concentrated sulfuric acid, the reaction of cyclocondensation does occur. Under these
2
5
conditions, the content of secondary product 3a increases a little (10%). When we increase the reaction time
6 h) in this solvent in the presence of H SO , the amount of quinazolinedione 3a increases even more. In
(
2
4
absolute methanol, in the presence of iodine the reaction proceeds very rapidly, and after 5-20 min the product of
oxidative cyclocondensation 2a is formed (45-58% yield); in this case, we do not observe formation of
compound 3a. An increase in the reaction time did not substantially affect the product yield. Thus the results
obtained show that in order to carry out oxidative cyclocondensation, we need the presence of a
solvent/oxidizing agent of the DMSO type [25], dehydrating agents, and in absolute methanol we need the
presence of molecular iodine as an oxidizing agent. In order to carry out cyclocondensation, we need the
presence of acids, the role of which involves catalysis of the oxidation process.
With the aim of studying the effect of temperature on the course of this reaction, we carried it out at
temperatures of 0°C, 25°C, 80°C, 140°C in DMSO in the presence of concentrated H SO or P O . We might
2
4
2
5
hypothesize that if the reaction is carried out in the presence of sulfuric acid, along with the increase in yield of
product 2, the yield of quinazolinedione 3a would sharply increase due to acid hydrolysis of the starting
compound. However, the experiments showed that the content of compound 3 did not appreciably increase
(
Table 2).
When the reaction is carried out in the presence of P O , the product yields are lower than when using
2
5
sulfuric acid, but formation of product 3a is less than in the second case. On the whole, raising the temperature
leads to an increase in the yield of reaction product, and accordingly the conversion of the starting compound to
the product increases.
The yield of reaction products sharply increases as the temperature is raised from 0 to 25°C. Further
increase in the reaction temperature up to 140°C smoothly increases the product yield. The results obtained
suggest that it is advisable to carry out oxidative cyclocondensation at room temperature, since in this case, there
are no secondary compounds and the target product is easily isolated from the reaction mixture.
With the aim of studying the electronic effects of substituents on the aromatic ring of 2-thioxo-4-
quinazoline and to expand the range of application of the reaction, we studied oxidative cyclocondensation of 6-
methyl-, 6-bromo-, 6-nitro-, and 7-nitro-2-thioxo-4-quinazolones 1b-e in DMSO in the presence of concentrated
H SO at room temperature. 6-Methyl-2-thioxo-4-quinazolone (1b) under these conditions undergoes oxidative
2
4
cyclocondensation, and the corresponding thiadiazolodiquinazolinedione 2b is readily formed in 75% yield.
Under analogous condition, thioxo-4-quinazolones 1c-e do not react. Instead of the expected products, the
corresponding 6-bromo-, 6-nitro-, and 7-nitroquinazoline-2,4-diones 3b-d are formed.
O
Me
N
R = 6-Me
N
N
O
N
R
S
Me
O
O
NH
2b
R
N
H
S
R = 6-Br, 6-NO , 7-NO
2
2
NH
1
b–e
N
H
O
3
b–d
1
b R = 6-Me, 1c, 3b R = 6-Br, 1d, 3c R = 6-NO
2
, 1e, 3d R = 7-NO
2
5
42

TABLE 2. Dependence of Yield of Product 2 on Temperature and Solvent*
Conversion
of starting
compound, %
Yield, %
Conversion
of starting
compound, %
Yield, %
Т, °С
Т, °С
2
a
3a
2a
3a
2
2
DMSO + P
2
O
5
*
2 4
DMSO + H SO *
0
10
56
66
77
10
55
65
74
0
0
0
30
76
90
30
68
81
90
0
8
9
2
8
5
0
25
80
traces
3
1
40
140
100
10
_
*
*
______
Reaction time: 4 h.
Solvent + oxidizing agent.
2
Formation of the cyclocondensation products from compounds 1c-e was not observed even when the
temperature was raised (140°C) and the reaction time was increased (10 h).
The data obtained allow us to conclude that electron-acceptor substituents or substituents with a -I effect
hinder the occurrence of the reaction, while electron-donor substituents favor oxidative cyclocondensation. Such
an effect from electron-acceptor substituents is probably connected with their strong negative inductive and
mesomeric effects, i.e., in this case delocalization of electron density on the sulfur atom occurs through the
conjugation chain, passing through the pyrimidine and benzene rings. As a result, the C–S bond is polarized to a
greater degree than in 2-thioxo-4-quinazoline itself. This facilitates breaking of this bond when treated with an
oxidizing agent, as in the case of compound 1c.
O
O
N
O
NH
SH
N
Thus the course of the reaction of oxidative cyclocondensation of 2-thioxo-4-quinazoline derivatives is
affected substantially by the electronic effect of the substituents. When an electron-donor substituent is
introduced at the 6 position of the aromatic ring, the reaction proceeds readily and the oxidative
cyclocondensation product is obtained in good yield. Introducing electron-acceptor substituents enhances the
oxidation and hydrolysis processes, and leads to formation of quinazoline-2,4-dione derivatives 3b-d.
EXPERIMENTAL
The IR spectra were obtained on a UR-20 spectrometer in KBr disks and on an IK-29 in alcoholic
solution; the UV spectra were taken on a Hitachi EPS-ST spectrometer (ethyl alcohol as the solvent). The mass
1
spectra were taken on an MKh-1303, MKh-1321, and MKh-1310 spectrometer; the H NMR spectra were taken
on a JNM-4H-100 (100 MHz) and a Tesla BS-567A, internal standards TMS, HMDS (0.05 ppm). The R values
f
were determined on Silufol UV-254. The visualizing agents were iodine vapor, UV light, KMnO +H SO +H O
4
2
4
2
(
0.5 g + 2 ml + 48 ml). The solvents were purified and dried according to the procedure in [26].
2
6
-Thioxo-4-quinazolone (1a) was synthesized by the procedure in [27].
-Methyl-2-thioxo-4-quinazolone (1b). Ammonium thiocyanate (1.65 g, 20 mmol) and conc. HCl
(
1.2 ml) were added to a solution of 5-methylanthranilic acid (3 g, 20 mmol) in o-xylene. The mixture was
boiled for 6 h and then cooled down. The precipitate was filtered out, washed with water, and dried. The
5
43

crystals obtained were dissolved in a 2 N NaOH solution (100 ml), then this was neutralized with dilute acetic
acid. The precipitate was filtered out, washed with water, and dried. Yield 3 g (80%); mp 288-290°C, R 0.61
f
-
1
(
[
acetone–benzene, 1:4). IR spectrum, ν, cm : 1680 (C=O), 3110, 3310 (NH). Mass spectrum, m/z (I, %): 192
M] (100), 177 [M–CH ] (30), 164 [M –CO] (70), 149 [M–HNCO] (45), 133 [M–HNCS] (40). H NMR
+ + 1 + + + 1
3
spectrum (CF COOH), δ, ppm: 6.90-8.70 (3H, m, arom. protons); 2.12 (3H, s, C –CH ). The data correspond to
3
(6)
3
the data given in [28].
6
-Bromo-2-thioxo-4-quinazolone (1c). Sodium thiocyanate (2.85 g, 35 mmol) and conc. HCl (2 ml)
were added to a solution of 5-bromoanthranilic acid (7.6 g, 35 mmol) in o-xylene. The mixture was boiled for
h and then cooled. The precipitate was filtered out, washed with water, and dried. The crystals obtained were
6
dissolved in a 2 N NaOH solution (150 ml), and then this solution was neutralized with dilute acetic acid. The
precipitate was filtered out, washed with water, and dried. Yield 3 g (30%); mp 323-325°C, R 0.74 (acetone–
f
benzene, 1:9). The data correspond to the data given in [28].
2
-Chloro-6-nitro-4-quinazolone. 2,4-Dichloro-6-nitroquinazoline (2.07 g, 10 mmol) was dissolved in
POCl (10 ml) and a few drops of triethylamine were added. The reaction mixture was boiled for 2 h at the
3
boiling point of phosphorus oxychloride. After this, the excess of the latter was distilled off and the precipitate
formed was washed with distilled water. A 10% NaOH solution (20 ml) was added to the residue, and the
mixture was boiled for 1 h. The solution was acidified with 10% HCl. The precipitate was filtered out and
recrystallized from alcohol. 2-Chloro-6-nitro-4-quinazolone (1.45 g, 74%) was obtained; mp 243-244°C
+
+
+
(
alcohol). Mass spectrum, m/z (I, %):* 225/227 [M] (100), 197/199 [M–CO] (75), 189 [M–Cl] (55). The data
correspond to the data given in [29].
6
-Nitro-2-thioxo-4-quinazolone (1d). Potassium hydrogen sulfide (1.8 g, 25 mmol) was added to a
solution of 2-chloro-6-nitro-4-quinazolone (4.5 g, 20 mmol) in aqueous alcohol (1:3) (100 ml). The mixture was
heated in a water bath at 85-90°C for 4 h and then cooled and diluted with water. The precipitate was filtered
out, washed with water, dried, and recrystallized from alcohol. Yield 1.78 g (40%) of a substance with
-
1
mp 267-268°C, R 0.7 (methanol–chloroform, 1:5). IR spectrum, ν, cm : 1350 (NO), 1685 (CO), 3190, 3330
(
f
+
+
+
1
NH). Mass spectrum, m/z (I, %): 223 [M] (100), 195 [M–CO] (70), 144 [M–HNCS] (30). H NMR spectrum
(
CF COOH), δ, ppm: 7.10-8.70 (3H, m, arom. protons).
3
7
-Nitro-2-thioxo-4-quinazolone (1e). A mixture of 4-nitroanthranilic acid (2 g, 10 mmol) and
ammonium thiocyanate (1.1 g, 15 mmol) was melted at 200-220°C for 20 min. The mixture was cooled and
dissolved in 2 N NaOH; the undissolved precipitate was filtered out. The mother liquor was neutralized and the
precipitate was filtered out, washed with water, and dried. Yield of product 0.25 g (10%); mp 250-252°C
-
1
(
alcohol), R 0.6 (acetone–benzene, 2:5). IR spectrum, ν, cm : 1350 (NO), 1680 (CO), 3190, 3325 (NH). Mass
f
+ + + 1
spectrum, m/z (I, %): 223 [M] (100), 195 [M–CO] (55), 144 [M–HNCS] (45). H NMR spectrum
CF COOH), δ, ppm: 7.20-8.85 (3H, m, arom. protons). The data correspond to the data given in [29].
(
3
8
H,15H-1,2,4-Thiadiazolo[3,2-b:5,4-b']diquinazoline-8,15-dione (2a). For methods A, B, see [24]. C.
Iodine (2.54 g, 15 mmol) was added to a solution of 2-thioxo-4-quinazolone (1.78 g, 10 mmol) in absolute
methanol (30 ml) while boiling. The reaction mixture was boiled for 15 min, cooled down, and diluted with
water. The aqueous solution was boiled until the dark-brown color disappeared. The solution was cooled down
and the precipitate was filtered out, washed with water, recrystallized from DMF, and dried. Yield of product
5
8%. The physicochemical and spectral data for the product obtained were identical to the data in [24].
,10-Dimethyl-8H,15H-1,2,4-thiadiazolo[3,2-b:5,4-b']diquinazoline-8,15-dione (2b). Conc. H SO
2
2
4
(
2 ml) was added with stirring to a solution of compound 1b (1.90 g, 10 mmol) in DMSO (10 ml). The mixture
was stirred for 4 h. The precipitate was filtered out, washed with water and then with DMF, and dried. Yield of
-
1
product 75%; mp 267-268°C, R 0.46 (acetone–benzene, 2:3). IR spectrum, ν, cm : 1685 (CO) (as a broadened
f
+
+
+
band). Mass spectrum, m/z (I, %): 348 [M] (100), 320 [M–CO] (82), 290 (46), 275 [M] (100). Found, %:
C 68.40; H 3.72; N 17.59. C H N O S. Calculated, %: C 68.35; H 3.79; N 17.72.
1
8
12
4
2
_
*
______
3
5
The values of m/z are given for ions with the isotope Cl.
5
44

2
-Oxoquinazolones 3b-d were obtained similarly by oxidative cyclocondensation of 6-bromo-, 6-nitro-,
7
-nitro-2-thioxo-4-quinazolones 1b-e. The properties of compounds 3b-d correspond to those described in [29].
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