Synthesis, properties, and mass-spectrometric fragmentation of 2-thio derivatives of 3-arylquinazolin-4-ones

Article abstract of DOI:10.1007/s10593-007-0052-7

We have studied the reactions of alkylation, oxidation, and hydrolysis of 3-aryl-2-thioxoquinazolin-4-ones. Alkylation in an alkaline medium occurs exclusively at the sulfur atom. Oxidation by hydrogen peroxide leads to formation of 3-arylquinazoline-2,4-diones. The latter are also obtained in base or acid hydrolysis of the synthesized S-alkyl derivatives. When 3-aryl-2-thioxoquinazolin-4-ones are reacted with iodine, we obtain the disulfides, while the reaction with chlorine in hydrochloric acid leads to 2-chloroquinazolin-4-ones. Studying the mass spectrometric behavior of the compounds obtained made it possible to observe in the gas phase ring-chain isomerization of the heterocyclic ring, and also S-N migration of the propargyl radical in molecular ions of the S-propargyl derivatives.

Full text of DOI:10.1007/s10593-007-0052-7

Chemistry of Heterocyclic Compounds, Vol. 43, No. 3, 2007
SYNTHESIS, PROPERTIES, AND MASS-SPECTROMETRIC FRAGMENTATION
OF 2-THIO DERIVATIVES OF 3-ARYLQUINAZOLIN-4-ONES
Yu. A. Azev1, B. V. Golomolzin1, T. Dyulcks2, N. A. Klyuev3, and Yu. G. Yatluk1
We have studied the reactions of alkylation, oxidation, and hydrolysis of 3-aryl-2-thioxoquinazolin-
4-ones. Alkylation in an alkaline medium occurs exclusively at the sulfur atom. Oxidation by hydrogen
peroxide leads to formation of 3-arylquinazoline-2,4-diones. The latter are also obtained in base or acid
hydrolysis of the synthesized S-alkyl derivatives. When 3-aryl-2-thioxoquinazolin-4-ones are reacted
with iodine, we obtain the disulfides, while the reaction with chlorine in hydrochloric acid leads to 2-
chloroquinazolin-4-ones. Studying the mass spectrometric behavior of the compounds obtained made it
possible to observe in the gas phase ring–chain isomerization of the heterocyclic ring, and also S–N
migration of the propargyl radical in molecular ions of the S-propargyl derivatives.
Keywords: 3-aryl-2-thioxoquinazolin-4-ones, alkylation, hydrolysis, mass-spectrometric fragmentation,
oxidation, skeletal rearrangements, thermolysis.
The quinazoline ring is an essential part of many natural alkaloids [1]. Among quinazoline derivatives
we find compounds with diverse biological activity (hypotonic, antiallergic, antibacterial, anthelmintic) [2].
Recently there has been an active search for antagonists of folic and isofolic acids, which are cell mitosis
inhibitors [3, 4]. The antitumor [2] and radioprotective [5, 6] properties of quinazoline derivatives have been
studied. It was shown earlier [6] that the radioprotective activity of 2-aminoalkylthio derivatives of
3-phenylquinazolin-4-one can be optimized by changing the alkyl chain in the position 2, and the duration of this
effect probably depends on the aryl group in the position 3. It has been hypothesized that the N-arylquinazoline
moiety facilitates penetration of the substance into the cell and that the aminothiol formed after hydrolytic
decomposition of the molecule exerts a radioprotective effect.
The aim of this work was to study new synthesis routes, chemical conversions, and mass-spectrometric
characteristics of derivatives of aryl-2-thioxoquinazolin-4-ones.
We synthesized the starting 3-aryl-2-thioxoquinazolin-4-ones 1a-d by condensation of anthranilic acid with
arylthioureas according to the method in [7]. The presence of a 2-thioxo group within their molecules results in more
opportunities for functionalization of the arylquinazolones. Thus as a result of oxidation of 3-(4-methyl-phenyl)-2-
thioxoquinazolin-4-one (1b) by hydrogen peroxide in alkaline medium, we obtained 3-(4-methyl-
phenyl)quinazoline-2,4-dione (2b) (Scheme 1), the structure of which has been confirmed by an alternate synthesis
from anthranilic acid and phenyl isocyanate [5]. At the same time, when alkaline solutions of the thiones 1a,c,d were
treated with a solution of iodine in 10% KI according to the method described in [8], the disulfides 3a,c,d were
obtained.
__________________________________________________________________________________________
2
1Ural State Technical University, Ekaterinburg 620002, Russia; e-mail: azural@dialup.utk.ru. Bremen
3
University, Germany D28334; e-mail: duelcks@chemie.uni-bremen.de. Institute of Ecology and Evolution
Problems, Russian Academy of Sciences, Moscow 117071. Translated from Khimiya Geterotsiklicheskikh
Soedinenii, No. 3, pp. 440-446, March, 2007. Original article submitted September 7, 2005; revised September 18,
2006.
356
0009-3122/07/4303-0356©2007 Springer Science+Business Media, Inc.

We know that methods involving chlorination of the corresponding thiones in aqueous medium are used
for synthesis of sulfonyl chlorides [9]. In studying oxidation of a suspension of the compounds 1a,b,d by
chlorine in a 10% HCl solution, we found a simple route for synthesis of 3-aryl-2-chloroquinazolin-4-ones
4a,b,d. The reaction probably occurs through a step of formation of the corresponding intermediate sulfonyl
chloride, which is converted to the 2-chloro derivative 4 (Scheme 1), analogously to the mechanisms described
in [9, 10].
Scheme 1
SR1
H
S
SO2Et
R
N
N
N
R1–X
Cl2/H2O
N
N
N
R
R
O
O
O
9d
1a–d
5a, 6a–d, 7d, 8a,d
+
–
H (OH )
O
H
N
O
H2O2
N
O
N
R
N
N
I2/KI
R
O
Cl2/HCl
10b,d
2a,b,d
S
N
O
Cl
NH
N
O
N
O
R
N
2
R
3a,c,d
4a,b,d
a R = Ph, b R = 4-MeC6H4, c R = 4-MeOC6H4, d R = 4-ClC6H4; 5 R1 = CH2CH2NEt2;
6 R1 = CH2C CH; 7 R1 = Et, 8 R = CH2CH2OH; X = Cl, Br, I
2-Alkylthio derivatives 5-8 were obtained as a result of the reaction of thiones 1 with alkyl halides in
alkaline solution at room temperature, while 3-(4-chlorophenyl)-2-ethylsulfonylquinazolin-4-one (9d) was
formed when quinazolone 7d is oxidized by chlorine in water.
The alkylthio derivatives 6a,b are hydrolyzed when heated in 15% solutions of HCl or NaOH, yielding the
known 3-arylquinazoline-2,4-diones 2a,b, which confirms the structure of the former as the S-alkyl rather than
the N-alkyl derivatives.
We found that when compounds 8a,d are heated at a temperature of 175-180°C for 30 min,
3-arylquinazolinediones 2a,d are formed in 30% yield. Such a conversion can be the result of intramolecular
nucleophilic attack on the terminal OH group of the alkyl substituent at the C(2) atom of the quinazoline ring with
formation of the cyclic intermediate 11, which then is cleaved according to Scheme 2.
The chloro derivatives 4 obtained in this work can be a convenient starting material for synthesis of
diverse 2-substituted 3-arylquinazolin-4-ones. Thus as a result of brief heating of chloro derivatives 4b,d with
morpholine in ethanol, the morpholino derivatives 10b,d are formed in 35-40% yield.
357

In studying the mass spectra of the propargyl derivatives of 6, we observed unusual fragmentation of the
molecular ion. In the mass spectra of these compounds, regardless of the structure of the aryl substituent, we
observe an intense peak with m/z 157. By high-resolution mass spectrometry, it was established that cleavage of
aryl isothiocyanate [ArNCS] from molecule 6 always leads to formation of a fragment having the composition
C10H7NO (found: m/z 157.052; calculated: m/z 157.0527, δ 0.3 ppm). Furthermore, determination of the
metastable ions (DADI method) showed that ions with m/z 263, 253, 234, 221, and 157 are formed directly from
the molecular ion 6a.
Scheme 2
O
S
H
N
N
OH
–
S
S
∆
N
N
R
R
O
O
8a,d
11
H
N
O
N
R
O
2a,d
The proposed structure for 6a as the alkylthio derivative A (see Scheme 3) is supported by the presence of
the following ions in the mass spectrum: m/z 253 [M–C3H3]+, m/z 221 [M–SCH2CCH]+, and m/z 194 [(M–
SCH2CCHHCN]+. At the same time, the appearance of the ions m/z 157 [M–SCN–C6H4R]+ (C10H7NO with δ 0.3
ppm) and [M–SC2H2]+ (234.0792, for C15H10N2O: 234.0793, δ 0.3 ppm) can be explained only as the result of
partial rearrangement of the molecular ion. In this case, detachment of the SC2H4 fragment is possible from the
cyclic structure B, while detachment of the fragment SCN–C6H4R calls for retro Diels–Alder cleavage
Scheme 3
.
+
221
N
253
S
.
+
.
N
O
S
N
O
+
N
O
S
N
N
B
A
C
NCS
6a
– SC2H2
–
234.0792
157.052
358

of the isomeric form of the molecular ion C. The thione form C also explains formation of the ion [M–CHO]+
(m/z 263), since it has a distorted boat conformation. Formation of such an isomer can be analogous to high-
temperature rearrangement of allyl ethers of phenols or enols to form isomeric C-allyl derivatives (O–Alk → C–
Alk), known as the Claisen rearrangement. Similar high-temperature rearrangements have been described for
heterocyclic derivatives [11]. However, we must note that the mass spectrometric rearrangement S–Alk → N–
Alk of the propargyl derivatives which we observed is not a high-temperature process, since the ratio of the
intensities of the molecular ion and the ion with m/z 157 [M–SCNArR]+ is practically constant over a broad
temperature range.
The examples given for mass spectrometric fragmentation confirm that migration of the alkyl group from
the S atom to the N(1) atom of quinazoline is possible for the S-propargyl derivatives, capable of forming a six-
center complex.
In conclusion, we should emphasize that in this work we have tested different synthetic routes for novel
3-arylquinazolines. The compounds obtained are of independent interest, and can also be studied as carriers for
different biologically active groups. We have observed novel chemical (thermal) transformations of quinazolines
which may be of metabolic interest. As a result of studying mass spectrometric fragmentation of 2-thio
derivatives of 3-arylquinazolone, we have observed mass spectrometric skeletal rearrangements for
2-thiopropargyl derivatives of 3-arylquinazolones.
TABLE 1 Derivatives of 3-N-Arylquinazol-4-one
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C
Yield, %
C
H
N
3а
3c
C28H18N4O2S2
66.2
66.4
63.3
63.6
58.2
58.4
65.4
65.5
66.5
66.5
57.5
57.8
67.9
68.0
69.7
69.8
70.5
70.6
66.9
67.1
62.2
62.5
60.5
60.7
64.1
64.4
57.6
57.7
54.9
55.1
70.8
71.0
3.8
3.6
4.0
3.9
2.6
2.8
3.5
3.5
4.0
4.1
2.6
2.8
6.6
6.7
4.0
4.1
4.5
4.6
4.6
4.4
3.4
3.4
3.9
4.1
4.8
4.7
3.9
3.9
3.8
3.8
6.1
6.0
9.9
250-251
260-261
262-263
112-113
125-126
149-150
77-78
30
30
25
20
25
45
45
50
45
45
55
40
40
40
45
30
35
11.1
C30H22N4O4S2
C28H16Cl2N4O2S2
C14H9ClN2O
C15H11ClN2O
C14H8Cl2N2O
C20H23N3OS
9.5
9.9
9.5
9.7
10.7
10.9
10.0
10.3
9.6
9.6
11.6
11.9
9.6
9.6
9.0
9.1
9.4
9.7
8.5
8.6
8.6
8.8
9.3
9.4
8.2
8.4
8.2
8.0
13.0
13.1
12.1
12.3
3d
4a
4b
4d
5а
6а
6b
6c
C17H12N2OS
184-185
157-159
193-194
195-196
157-158
98-99
C18H14N2OS
C18H14N2O2S
C17H11ClN2OS
C16H13ClN2OS
C16H14N2O2S
C16H13ClN2O2
C16H13ClN2O3S
C19H19N3O2
6d
7d
8а
8d
9d
10b
10d
161-162
185-186
133-134
140-141
C18H16ClN3O2
63.0
63.2
4.6
4.7
359

EXPERIMENTAL
The mass spectra were taken on a double-focusing Finnigan MAT 8200 mass spectrometer using a direct
injection system with ionization energy 70 eV.
Oxidation of 3-(4-Methylphenyl)-2-thioxoquinazolin-4-one (1) by Hydrogen Peroxide. A 30% aqueous
solution of H2O2 (22 ml) was slowly added to a solution of compound 1b (10.8 g, 40 mmol) (obtained according to
[7]) in a 10% aqueous solution of KOH (70 ml), with heating up to 70°C and stirring; the mixture was boiled for 15
min and then cooled down, and then concentrated HCl was added down to pH 1. The precipitate of 2b formed was
filtered out and recrystallized from butanol. Yield 45%; mp 258°C (mp 258°C [3, 5, 8]).
Bis(2-quinazolyl) Disulfide 3a. A solution of iodine (2.5 g, 10 mmol) in a 10% aqueous solution of KI
(75 ml) was added to a solution of of compound 1a (10 mmol) in a 5% aqueous solution of KOH (25 ml) at
20°C. The precipitate formed of the disulfide 3a was filtered out and recrystallized from ethanol.
Disulfides 3c,d were obtained similarly.
Alkylation of 3-Aryl-2-thioxoquinazolin-4-ones. Compound 1 (10 mmol) was dissolved in a 5% NaOH
solution (50 ml) and filtered. A solution of the corresponding alkyl halide (ClCH2CH2NEt2, BrCH2CCH, IEt, or
ClCH2CH2OH) in water (10 ml) was added to the filtrate. The reaction mass was stirred at room temperature for
1 h 30 min to 2 h. The precipitate formed of products 5-8 was filtered out and recrystallized from aqueous
ethanol (see Table 1). Mass spectrum, m/z (Irel, %): 6a - 292 [М]+ (58), 291 (98), 263 (5), 253 (19), 234 (17), 221
(19), 157 (100); 6b – 306 [М]+ (64), 305 (98), 273 (8), 248 (18), 235 (19), 224 (7), 157 (100); 6c – 322 [М]+
(87), 321 (91), 283 (11), 251 (16), 180 (6), 157 (100); 6d – 326 [М]+ (45), 325 (65), 291 (12), 255 (17), 252 (9),
192 (8), 157 (100).
3-(4-Chlorophenyl)-2-ethylsulfonylquinazolin-4-one (9d). Gaseous chlorine was passed through a
suspension of ethylthioquinazolone 7d (1.0 mmol) in water (10 ml) at 5-7°C for 25-30 min. The precipitate of
the sulfone was filtered out, washed with ethanol, and recrystallized from aqueous ethanol.
Hydrolysis of 2-Alkylthio Derivatives of 3-Arylquinazol-4-ones. A. A solution of the alkylthio
derivative 6a (146 mg, 0.5 mmol) was boiled in of 15% aqueous HCl (10 ml) for 1 h. The reaction mass was
cooled down, and the precipitate was filtered out and recrystallized from ethanol. Yield of quinazolinedione 2a,
70 mg (30%); mp 272°C (mp 272°C [3, 8]).
B. A solution of compound 6b (153 mg, 0.5 mmol) in a 15% alcoholic NaOH solution (3 ml) was boiled
for 1 h; the reaction mass was filtered, the mother liquor was diluted with water 1:5, the precipitate formed of
compound 2b was filtered out and reprecipitated from ethanol by water. Yield 50 mg (20%); mp 258°C
(mp 258°C [3, 5, 8]).
Thermolysis of 2-(2-Hydroxyethylthio)-3-phenylquinazol-4-one (8a). Compound 8a (1.0 mmol) was
heated at 175-180°C for 1 h. The quinazolinedione 2a formed was extracted from the solid mass with butanol.
The solution was cooled down and the precipitate was filtered out. Yield 70 mg (15%); mp 272°C (mp 272°C [3,
5, 8]).
Thermolysis of compound 8d was carried out similarly. Yield of compound 8d 25%; mp 295°C
(mp 295°C [3, 5, 8]).
2-Chloro-3-phenylquinazolin-4-one (4a). Gaseous chlorine was passed through a suspension of
compound 1a (1.0 mmol) in 10% HCl (10 ml) at 5-10°C for 45-50 min. The precipitate of compound 4 was
filtered out and recrystallized from ethanol.
2-Chloro derivatives 4b,d were obtained similarly (see Table 1).
3-(4-Methylphenyl)-2-(N-morpholyl)quinazolin-4-one (10b). A solution of chloro derivative 4b
(0.05 mmol) and morpholine (3.0 mmol) in ethanol (2 ml) was boiled for 1 h. The reaction mass was cooled
down; the precipitate was filtered out and washed with water.
Compound 10d was obtained similarly (see Table 1).
360

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