Synthesis of 3-methylquinazolin-4(3H)-one derivatives

Article abstract of DOI:10.1134/S1070428012090126

Oxidation of 3-methyl-2-sulfanylquinazolin-4(3H)-one with chlorine dioxide under different conditions gave 2,2'-disulfanediylbis[3-methylquinazolin-4(3H)- one], 3-methyl-4-oxo-3,4-dihydroquinazoline-2-sulfonic acid, 3-methylquinazoline-2,4(1H,3H)-dione, 6

Full text of DOI:10.1134/S1070428012090126

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 9, pp. 1222–1225. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © O.M. Lezina, S.A. Rubtsova, V.A. Polukeev, A.V. Kutchin, 2012, published in Zhurnal Organicheskoi Khimii, 2012, Vol. 48, No. 9,
pp. 1223–1226.
Synthesis of 3-Methylquinazolin-4(3H)-one Derivatives
O. M. Lezinaa, S. A. Rubtsovaa, V. A. Polukeevb, and A. V. Kutchina
a Institute of Chemistry, Komi Research Center, Ural Division, Russian Academy of Sciences,
ul. Pervomaiskaya 48, Syktyvkar, 167982 Russia
e-mail: lezina-om@chemi.komisc.ru
b Vekton Closed Corporation, St. Petersburg, Russia
Received December 29, 2011
Abstract—Oxidation of 3-methyl-2-sulfanylquinazolin-4(3H)-one with chlorine dioxide under different condi-
tions gave 2,2′-disulfanediylbis[3-methylquinazolin-4(3H)-one], 3-methyl-4-oxo-3,4-dihydroquinazoline-2-sul-
fonic acid, 3-methylquinazoline-2,4(1H,3H)-dione, 6-chloro-3-methylquinazoline-2,4(1H,3H)-dione, and
N,N-diethyl-3-methyl-4-oxo-3,4-dihydroquinazoline-2-sulfonamide.
DOI: 10.1134/S1070428012090126
Quinazoline alkaloids exhibit a broad spectrum of
pharmacological activity, in particular anti-choline
esterase, antimalarial, choleretic, bronchodilator, sopo-
rific, diuretic, etc. [1]. Physiological activity of quinaz-
oline derivatives is primarily determined by the nature
of substituents in their molecules; therefore, introduc-
tion of new functional groups thereinto attracts strong
interest from both medical and chemical viewpoints.
Oxidative transformations of heterocyclic compounds
may be regarded as most interesting ways of their
modification.
benzene, acetic acid, acetonitrile, methanol, pyridine,
and diethylamine. Chlorine dioxide in a mixture with
atmospheric air was bubbled through the reaction mix-
ture. Taking into account that alkaline medium favors
transformation of thione isomer into thiol [5], potas-
sium hydroxide was added. Furthermore, addition of
alkali considerably improved the solubility of thiol I in
methanol. Compound I is poorly soluble in most
accessible solvents, except for DMSO. Vanadium cata-
lyst VO(acac)2 was used to increase the rate of oxida-
tion and selectivity of the process; this catalyst turned
out to be efficient in the oxidation with chlorine
dioxide of sulfoxides to sulfones [6] and of diphenyl
disulfide to benzenesulfonyl chloride [4]. In order to
identify some new compounds, thiol I was also oxi-
dized under analogous conditions with iodine which is
known to selectively oxidize thiols to disulfides [7].
The product composition and ratio were analyzed by
1H NMR spectroscopy on the basis of signal intensities
of the 5-H, 6-H, 7-H, and 8-H protons (see table).
In the present work we used 3-methyl-2-sulfanyl-
quinazolin-4(3H)-one (I) containing a structural frag-
ment intrinsic to quinazoline alkaloids to study the
possibility for obtaining new derivatives via its oxida-
tion with chlorine dioxide. The latter is produced on
a large scale for bleaching of cellulose and decon-
tamination of water and was shown to be a convenient
and efficient oxidant ensuring transformation of
alkane- and arenethiols into disulfides [2], S-alkyl thio-
sulfonates [3], and sulfonyl chlorides [4]. Oxidation of
heterocyclic thiols with ClO2 was not studied.
The oxidation of I with chlorine dioxide in metha-
nol gave 2,2′-disulfanediylbis[3-methylquinazoline-
4(3H)-one] (II) (Scheme 1). Addition of an equimolar
amount of potassium hydroxide allowed us to raise the
yield of disulfide II from 42 to 65% and reduce the
consumption of chlorine dioxide by half (from 1 to
0.5 mol, the conversion of thiol I being complete; see
table). The oxidation of I in methanol with 5 equiv of
iodine in neutral and alkaline media also afforded
disulfide II in the same yields as with chlorine dioxide,
Unlike alkane- and arenethiols, heterocyclic thiols
are characterized by diverse chemical properties due to
their ability to undergo thiol–thione tautomerism. The
state of tautomeric equilibrium depends on the solvent
nature [5]; therefore, we examined the composition of
oxidation products of heterocyclic thiol I with chlorine
dioxide, obtained under different conditions (solvent,
reactant molar ratio, catalyst). As solvents we used
1222

SYNTHESIS OF 3-METHYLQUINAZOLIN-4(3H)-ONE DERIVATIVES
1223
Scheme 1.
O
Me
S
O
O
N
Me
SH
Me
S
ClO2
S
N
O
N
N
N
N
N
N
H
Me
I
II
O
N
O
O
Me
Me
O
Cl
Me
O
ClO2
ClO2
ClO2
N
N
N
SO3H
N
N
H
H
III
IV
V
ClO2, H+
Et2NH
I
IV
O
O
N
Me
Me
ClO2
N
N
I
+ Et2NH·HCl
N
SO2Cl
SO2NEt2
A
VI
but the conversion of compound I did not exceed 66%.
The H NMR spectrum of II lacked NH signal
product (according to the 1H NMR data). Unlike initial
thiol I, two carbonyl absorption bands were observed
in the IR spectrum of IV (1689 and 1718 cm–1).
1
(δ 12.95 ppm) typical of the thione tautomer of the
13
initial compound. In the C NMR spectrum of II, the
A mixture of dione IV and 6-chloro-3-methyl-
quinazoline-2,4(1H,3H)-dione (V) at a ratio of ~2:1
was obtained by oxidation of I with 4 equiv of ClO2 in
acetonitrile; in the presence of VO(acac)2 as catalyst,
the ratio IV:V changed to 8:1. Dione V was formed as
the major product (85% in the product mixture) when
catalytic oxidation was carried out with the use of
7 equiv of chlorine dioxide. The position of chlorine in
the quinazoline ring (on C6) was determined by two-
dimensional NMR spectroscopy. The C6 signal in the
13C NMR spectrum of IV appeared at δC 122 ppm,
while in the spectrum of V, at δC 126 ppm due to
electron-withdrawing effect of the 6-Cl atom.
C2 signal was displaced upfield (δC 152.97 ppm)
relative to the corresponding signal of thiol I
(δC 175.41 ppm). Compound II displayed no C=S
absorption band at 1001 cm–1 in the IR spectrum, but
a band typical of C–S bond appeared at 690 cm–1.
3,4-Dihydro-3-methyl-4-oxoquinazoline-2-sulfonic
acid (III) was obtained when compound I was oxi-
dized with chlorine dioxide in benzene and pyridine at
a substrate-to-oxidant molar ratio of 1:3. The IR spec-
trum of the product contained absorption bands at
1255, 1226, and 1049 cm–1 due to symmetric and anti-
symmetric stretching vibrations of the SO2 group. In
the 13C NMR spectrum of III the C2 signal was located
in a weaker field (δC 157.24 ppm) relative to the C2
signal of II (δC 152.97 ppm). The relative concentra-
tion of sulfonic acid III in the reaction mixture ranged
from 30 to 45%, depending on he conditions.
As basic solvents we tried pyridine and diethyl-
amine. The oxidation of I with 3 equiv of ClO2 in
diethylamine at –10°C produced 52% of N,N-diethyl-
3-methyl-4-oxo-3,4-dihydroquinazoline-2-sulfonamide
(VI). The IR spectrum of VI contained absorption
bands belonging to stretching vibrations of the SO2
group (1172, 1377 cm–1), and the C2 nucleus in VI
resonated in a weaker field (δC 160.62 ppm) as com-
pared to II. The reaction is likely to involve interme-
diate formation of sulfonyl chloride A. However, we
failed to isolate it as individual substance in any sol-
Only traces of III were present in the reaction
mixtures obtained using acetic acid and methanol as
solvent. The reason is its easy quantitative transforma-
tion into 3-methylquinazoline-2,4(1H,3H)-dione (IV).
In the oxidation of I with 2 equiv of ClO2 in acetic
acid, quinazolinedione IV was formed as the only
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 9 2012

LEZINA et al.
1224
Oxidation of 3-methyl-2-sulfanylquinazolin-4(3H)-one (I) with chlorine dioxide and iodine
Product ratio, % (1H NMR data)
Conversion
of I, %
Solvent
Oxidant [O] Other reagents Ratio I:[O]
II
III
IV
V
Benzene
Pyridine
ClO2
ClO2
ClO2
ClO2
ClO2
ClO2
ClO2
ClO2
ClO2
ClO2
ClO2
I2
–
1:3
1:2
100
019
100
100
052
100
100
100
092
100
100
000
039
066
–
–
43
14
32
–
57
05
68
1000
23
57
78
–
–
–
–
–
1:3
–
–
Acetic acid
Acetonitrile
–
1:2
–
–
–
1:2
–
19
09
12
12
–
10
34
10
88
–
–
1:4
–
VO(acac)2
1:4
–
VO(acac)2
1:7
–
Methanol
–
1:1
42
65
–
50
35
89
–
KOH
0.1:0.5
1:2
–
–
–
11
–
–
–
1:1
–
–
I2
–
1:5
39
66
–
–
–
I2
KOH
1:5
–
–
–
vent, presumably because of its instability. Pyridine
lacks labile NH hydrogen atom; therefore, the oxida-
tion of I with ClO2 in pyridine was not accompanied
by addition of pyridine molecule to the substrate, but
a mixture of compounds III and IV was formed at
a ratio of ~1:2.
Aqueous chlorine dioxide was a commercial product;
its concentration was determined by titration according
to the procedure described in [8].
2,2′-Disulfanediylbis[3-methylquinazolin-4(3H)-
one] (II). a. Potassium hydroxide, 0.029 g (0.5 mmol),
was added to a solution of 0.1 g (0.5 mmol) of thiol I
in 40 ml of methanol, the mixture was stirred at room
temperature until it became homogeneous, and 0.018 g
(0.25 mmol) of chlorine dioxide (dried by passing
through gas-washing bottles charged with concentrat-
ed sulfuric acid and calcium chloride) in a mixture
with air was bubbled through the solution over
a period of 30 min. A white solid precipitated and was
filtered off, washed with methanol, and dried in air.
Yield 0.065 g (65%). IR spectrum ν, cm–1: 3433 br.w,
2939–3066 w, 1697 s (C=O), 1609 w, 1580 w, 1551 s,
1472 s, 1412, 1317 s, 1115 w, 1065 s, 771 s, 690.
1H NMR spectrum (CDCl3), δ, ppm: 3.93 s (3H,
NCH3), 7.43 d.d.d (1H, 6-H, J = 8.3, 8.0, 1.3 Hz),
7.53 d.d (1H, 8-H, J = 7.0, 1.3 Hz), 7.69 d.d.d (1H,
7-H, J = 8.3, 7.0, 1.4 Hz), 8.25 d.d (1H, 5-H, J = 8.0,
To conclude, we have synthesized new compounds
II, III, and VI, as well as previously described quinaz-
olinediones IV and V, by oxidation of 3-methyl-2-
sulfanylquinazolin-4(3H)-one (I) with chlorine diox-
ide. The oxidation of I with ClO2 in neutral and alka-
line media gives disulfide II and sulfonic acid III in
moderate yields; the reactions in acid or strongly polar
media lead to dione IV, while in acetonitrile, to dione
V, in quantitative yield. The use of VO(acac)2 as
catalyst hampers chlorination in the initial steps but
favors stepwise formation of compounds IV and V.
EXPERIMENTAL
The IR spectra were recorded from thin films or
KBr pellets on a Shimadzu IR Prestige 21 spectrometer
with Fourier transform. The melting points were meas-
ured on a Gallenkamp-Sanyo melting point apparatus.
13
1.4 Hz). C NMR spectrum (CDCl3), δC, ppm: 31.04
(NCH3), 119.57 (C4a), 126.70 (C6, C8), 127.07 (C5),
134.47 (C7), 147.07 (C8a), 152.97 (C2), 161.85 (C4).
Found, %: C 56.40; H 3.63; N 14.50; S 16.74.
C18H14N4O2S2. Calculated, %: C 56.53; H 3.69;
N 14.65; S 16.77.
1
The H and 13C NMR spectra were run on a Bruker
Avance-II-300 instrument at 300.17 and 75.42 MHz,
respectively. The elemental compositions were deter-
mined using an EA 1110 CHNS-O automatic analyzer.
b. Potassium hydroxide, 0.029 g (0.5 mmol), was
added to a solution of 0.1 g (0.5 mmol) of thiol I in
10 ml of methanol, the mixture was stirred at room
3-Methyl-2-sulfanylquinazoline-4(3H)-one (purity
99%) was synthesized at the Vekton closed corporation.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 9 2012

SYNTHESIS OF 3-METHYLQUINAZOLIN-4(3H)-ONE DERIVATIVES
1225
temperature until it became homogeneous, a solution
of 0.66 g (2.5 mmol) of iodine in 30 ml of methanol
was added dropwise over a period of 30 min, and the
mixture was stirred for 15 min more. The white precip-
itate was filtered off, washed with methanol, and dried
in air. Yield 0.066 g (66%).
13C NMR spectrum (DMSO-d6), δC, ppm: 27.22
(NCH3), 115.03 (C4a), 117.40 (C8), 126.15 (C5), 126.44
(C6), 134.72 (C7), 138.20 (C8a), 150.11 (C2),
161.22 (C4).
N,N-Diethyl-3-methyl-4-oxo-3,4-dihydroquinaz-
oline-2-sulfonamide (VI) was synthesized according
to the procedure described above in c using diethyl-
amine (25 ml) as solvent and 0.070 g (1 mmol) of
chlorine dioxide (10°C, 45 min). The precipitate of
diethylamine hydrochloride was filtered off, most part
of the filtrate was evaporated under reduced pressure,
and the residue was extracted with methylene chloride.
The extract was evaporated, and the residue was re-
crystallized from DMSO and H2O. Yield 0.080 g
(52%), white flakes. IR spectrum (KBr), ν, cm–1: 1678
3-Methyl-4-oxo-3,4-dihydroquinazoline-2-sulfon-
ic acid (III). c. Chlorine dioxide, 0.11 g (1.5 mmol), in
a mixture with air was bubbled over a period of 1.5 h
through a solution of 0.1 g (0.5 mmol) of thiol I in
60 ml of benzene. The mixture was evaporated under
reduced pressure, the residue was washed with water,
and the precipitate was filtered off and dried. The
product was a mixture of compounds III and IV
1
(fraction of III 45% according to the H NMR data).
1
(C=O), 1377, 1172 (SO2). H NMR spectrum
The IR and NMR spectral parameters were identified
from the spectra of its mixture with IV. IR spectrum
(KBr), ν, cm–1: 3404 br.w, 2981–3180, 1708 s (C=O),
1639 s (C=N), 1570, 1531, 1485, 1282 (C–N), 1255 s
(SO2), 1226 s (SO2), 1049 s (SO2), 972, 817, 763, 648,
(DMSO-d6), δ, ppm: 1.17 t (6H, CH2CH3), 3.37 s (3H,
NCH3), 3.50 br.m (4H, CH2CH3), 7.43 t (1H, 6-H, J =
7.04 Hz), 7.51 d (1H, 8-H, J = 8.05 Hz), 7.77 t (1H,
7-H, J = 7.08 Hz), 8.07 d.d (1H, 5-H, J = 7.95,
1.39 Hz). 13C NMR spectrum (DMSO-d6), δC, ppm:
14.32 (CH2CH3), 28.48 (NCH3), 50.24 (CH2CH3),
118.73 (C4a), 125.51 (C6), 126.17 (C8), 126.27 (C5),
134.36 (C7), 146.87 (C8a), 160.62 (C2), 160.83 (C4).
Found, %: C 53.08; H 6.07; N 14.70; S 11.10.
C13H14N4O3S. Calculated, %: C 52.87; H 5.80;
N 14.23; S 10.86.
1
634. H NMR spectrum (DMSO-d6), δ, ppm: 3.56 s
(3H, NCH3), 7.63–7.68 m (1H, 6-H), 7.74 d (1H, 8-H,
J = 8.22 Hz), 7.89–7.95 m (1H, 7-H), 8.21 d (1H, 5-H,
J = 7.93 Hz), 8.82 s (1H, OH). 13C NMR spectrum
(DMSO-d6), δC, ppm: 34.15 (NCH3), 120.75 (C4a),
124.60 (C6), 126.25 (C8), 127.75 (C5), 134.92 (C7),
144.53 (C8a), 157.24 (C2), 159.95 (C4).
3-Methylquinazoline-2,4(1H,3H)-dione (IV) was
synthesized according to the procedure described
above in c using glacial acetic acid (20 ml) as solvent
and 0.070 g (1.0 mmol) of chlorine dioxide; reaction
time 1 h. The solvent was removed under reduced
pressure, and the dry residue was washed with a satu-
rated solution of sodium hydrogen carbonate to neu-
tralize residual acid and dried under reduced pressure.
Yield 0.084 g (92%), mp 242–243°C (from DMSO,
H2O); published data [9]: mp 242–243.4°C.
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(V). d. Thiol I, 0.1 g (0.5 mmol), was dissolved in
30 ml of acetonitrile, 0.007 g (5 mol %) of VO(acac)2
was added, and the mixture was stirred on a magnetic
stirrer until it became homogeneous. Chlorine dioxide,
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 9 2012