Cyclization of 2-benzoylamino-N-methyl-thiobenzamides to 3-methyl-2-phenylquinazolin-4-thiones

Article abstract of DOI:10.1002/jhet.5570430521

Acylation of 2-amino-N-methyl-thiobenzamide with substituted benzoyl chlorides has been used to synthesize the corresponding 2-benzoylamino-N- methylthiobenzamides. Subsequent sodium methoxide-catalyzed ring closure gives the corresponding 3-methyl-2-phen

Full text of DOI:10.1002/jhet.5570430521

Sep-Oct 2006
Cyclization of 2-Benzoylamino-N-methyl-thiobenzamides to 3-Methyl-
2-Phenylquinazolin-4-thiones
1281
Ji í Hanuseka*, Pavel Rosab, Pavel Drabinaa and Miloꢀ Sedláka
aDepartment of Organic Chemistry, Faculty of Chemical Technology, University of Pardubice, Nám. ꢁs. legií
565, 532 10 Pardubice, Czech Republic
bANIVEG CZ s r.o., 8. kvꢂtna 165, 410 02 Lovosice, Czech Republic
Received December 12, 2005
S
S
C
CH3
CH3
N
N
CH3ONa
R1
H
NH
C
N
R1
O
Acylation of 2-amino-N-methyl-thiobenzamide with substituted benzoyl chlorides has been used to
synthesize the corresponding 2-benzoylamino-N-methylthiobenzamides. Subsequent sodium methoxide-
catalyzed ring closure gives the corresponding 3-methyl-2-phenylquinazoline-4-thiones. These compounds
were characterized by means of their 1H- and 13C-NMR spectra. The kinetics of the cyclization reaction has
been followed with UV-VIS spectroscopy at 100 °C in methanolic solutions of sodium methoxide.
J. Heterocyclic Chem., 43, 1281 (2006).
In present work we have extended this study to 2-
benzoylamino-N-methyl-thiobenzamides. We have
chosen the way of constructing the heterocyclic skeleton
which consists in the acylation of 2-amino-N-methyl-
thiobenzamide with substituted benzoyl chlorides and
subsequent ring closure of the obtained 2-benzoylamino-
N-methyl-thiobenzamides (1a-f) in sodium methoxide to
give substituted 2-phenyl-3-methylquinazoline-4-thiones
(2a-f) (Scheme I).
Introduction.
Quinazoline-4-ones and their derivatives are well
known for their pharmacological activity [1]. Their
synthesis mostly starts from anthranilic acid derivatives,
in particular their N-acylamides [2,3]. The aim of the
present work is to synthesize the sulfur analogues of N-
benzoylaminoanthranilamides and to carry out their ring
closure to the corresponding 2-phenyl-3-methylquina-
zoline-4-thiones, which could show biological activity too
[4,5]. Quinazoline-4-thiones can be synthesized by
several ways: e.g. it is possible to transform the oxygen
derivative into its sulfur analogue by treating it with
phosphorus pentasulfide [6] or Lawesson’s reagent [7]. In
some cases it is also possible to make use of the reactivity
of suitably substituted isothiocyanates [8]. In our previous
Results and Discussion.
The starting 2-amino-N-methyl-thiobenzamide was
prepared by three-step synthesis from isatoic anhydride
and methylamine. Resulting 2-amino-N-methyl-
benzamide was in the second step converted to the
Scheme I
S
S
COCl
R
S
C
CH3
C
CH3
+
CH3
N
N
CH3ONa
N
TEA
R1
H
H
NH
C
NH2
N
R1
O
2a-f
1a-f
1-2
R1
a
b
c
d
e
f
4-OCH3 4-CH3
H
4-Cl 4-NO2 3-NO2
papers [9-11] we dealt with the synthesis, structure
and reactivity of 2-benzoylaminothiobenzamides, 2-[(N-
methyl-N-benzoyl)amino]thiobenzamides and products of
their cyclization in both basic and acidic medium.
corresponding pyridinium salt of 2-mercapto-2-thioxo-
2,3-dihydro-1H-2ꢀ5-benzo[1.3.2]diazaphosphinine-4-
thione by treatment with phosphorus pentasulfide [9], and
in the third step the pyridinium salt was transformed into

1282
J.Hanusek, P. Rosa, P. Drabina and M. Sedlák
Vol 43
the respective thioamide by our original hydrolysis
method in a toluene-water system. The benzoylation of
the 2-amino-N-methyl-thiobenzamide thus obtained was
carried out by treatment with commercial benzoyl
chlorides in acetone solvent. The reaction gives 2-
benzoylamino-N-methyl-thiobenzamides (1a-f). The ring
closure of (1a-f) to corresponding 2-(subst.phenyl)-3-
methylquinazoline-4-thiones (2a-f) is achieved by
refluxing in methanolic solutions of sodium methoxide
(Scheme I).
In order to optimize conditions for cyclization step, the
reaction of 1c and 1d was studied in detail using
methanolic solutions of sodium methoxide in the
concentration range of 0.01 – 0.35 mol·l–1 at 100 °C. We
found, that in contrast to ring closure reactions of similar
derivatives with or without methyl group at the nitrogen
adjacent to benzene ring [10] an elevated temperature is
needed for successful cyclization of 1a-f. The cyclization
rate has been found to depend nonlinearly on the
concentration of the sodium methoxide (Figure 1).
benzene ring (the so-called blind alley) and the terminal
nitrogen (CSNHCH3 group). The nucleophilic terminal
anion formed in the latter case attacks the carbonyl group
of the benzoyl moiety to give a tetrahedral intermediate,
which undergoes a proton transfer from nitrogen to
–
oxygen (In1– ꢀ In2 ) and then splits off hydroxyl anion to
produce 2-phenylquinazoline-4-thione. In contrast to the
similar 2-[(N-methyl-N-benzoyl)amino]thiobenzamides
[10], two protons can be split off in the starting
compounds 1a-f. The proton easier to split off is at the
nitrogen atom adjacent to the benzene ring (the
equilibrium constant K1), but the anion thus formed [N–]
cannot enter cyclization, so this is the so-called blind
–
alley. The concentration of the reactive anion [NCH3 ]
formed by deprotonation of the terminal CSNHCH3 group
is expressed by the equilibrium constant K2. Under
presumption that K1 >> K2, the Eq. (1) which describes
the reacting system can be modified to Eq. (2):
kc ꢀ K2 ꢀ
[
CH3ONa
]
(1)
(2)
kobs
=
1+ (K1 + K2 ) ꢀ
[
CH3ONa
]
kc ꢀ K2 ꢀ
[
CH3ONa
]
]
kobs
=
1+ K1 ꢀ
[
CH3ONa
Optimization using Eq. (2) leads to values of
parameters kc·K2(1c) = 9.49·10–2 l·mol–1·s–1, K1(1c) = 56
l·mol–1 and kc·K2(1d) = 2.62·10–1 l·mol–1·s–1, K1(1d) = 125
l·mol–1. The values of K1(1c) and K1(1d) are approx-
imately 3-5 times higher than values obtained in the case
of cyclization reactions of 2-benzoylaminothiobenza-
mides and 2-[(N-methyl-N-benzoyl)amino]thiobenza-
mides [10] at 25 °C. This relatively small increase in the
equilibrium constants of deprotonation is in accordance
with the low temperature sensitivity of the equilibria
involving the proton transfer [12]. A much larger
difference has been found out in the case of kinetic
parameters (the products kc·K2). While the ring closure of
2-[(N-methyl-N-benzoyl)amino]thiobenzamides is very
fast at the temperatures as low as 25 °C [10], the
relocation of methyl group from the nitrogen atom
adjacent to the benzene ring to the nitrogen atom of
thioamide group results in a retardation of the reaction by
several orders of magnitude. This retardation is mainly
due to the decrease in the equilibrium constant K2 (the
inductive effect of methyl group lowers the acidity of
thiobenzamide group by at least one order of magnitude).
Besides that, steric effect of the methyl group shields the
nucleophilic centre.
Figure 1. Dependences of kobs on c(CH3ONa) for cyclisation reaction of
1c and 1d.
From the course of experimentally found dependences
it follows that in this case the reaction order is equal to
one at low sodium methoxide concentrations and
gradually drops to zero at higher sodium methoxide
concentrations, which is characteristic of reactions with a
fast pre-equilibrium followed by the rate-limiting step.
The following Scheme II can be suggested for the said
ring closure.
The cyclization of the derivatives 1a-f can be
negatively affected also by intramolecular hydrogen bond
formation, which stabilizes the starting species (Figure 2).
In the sodium methoxide solutions used, a fast pre-
equilibrium deprotonation takes place first: a proton is
split off from both the nitrogen atom adjacent to the

Sep-Oct 2006
Cyclization of 2-benzoylamino-N-methyl-thiobenzamides
to 2-Phenyl-3-Methyl-3H-quinazolin-4-thiones
1283
Scheme II
S
S
S
C
CH3
C
CH3
CH3
N
N
N
CH3ONa
R1
R1
H
CH3OH
NH
C
NH
C
N
K2
R1
1a-f
2a-f
O
O
kc
CH3ONa
–OH
CH3OH
K1
S
S
S
CH3
OH
CH3
CH3OH
C
CH3
N
N
N
H
O
R1
N
N
H
R1
R1
N
C
O
–
–
In1
In2
The proton in hydrogen bond is bound in a relatively rigid
six-member ring, which is transformed into intermediate
In1 with a relatively low entropy loss. On the other hand,
slower, hence it has to be carried out at enhanced
temperatures (boiling under reflux or in a sealed ampoule
at 100 °C). The kinetic study carried out with two selected
derivatives shows that the order of reaction with respect to
methoxide anion (at its concentrations above 0.15 mol·l–1)
is zero: thus further increases in the methoxide
concentration do not lead to any acceleration of the
reaction.
–
in the case of the derivative carrying methyl group at the
nitrogen adjacent to benzene ring, where the hydrogen
bond cannot be formed and the system thus has a higher
number of degrees of freedom, the ring closure giving
–
intermediate In1 is connected with a substantially larger
entropy drop.
EXPERIMENTAL
S
ꢀ
N
C
CH3
General.
The H- and 13C-NMR spectra were measured at 360.14 and
ꢀ
N
1
H
90.57 MHz, respectively, at 25 °C, using a Bruker AMX
spectrometer in deuteriochloroform or hexadeuteriodimethyl
sulphoxide (DMSO-d6), and the chemical shifts are referenced to
tetramethylsilane (ꢀ(1H) = 0 ppm) and the solvent signal (ꢀ(13C)
= 39.6 ppm for DMSO-d6 and ꢀ(13C) = 77.0 ppm for CDCl3).
Kinetic measurements were carried out under pseudo-first-order
conditions on a HP UV/VIS 8453 Diode Array apparatus. Glass
ampoules were charged with solution of sodium methoxide in
methanol (20 ml) in the concentration range of 0.0025 – 0.32
mol·l–1 and 1 ml of methanolic solution of 1c or 1d (c = 1·10–3
mol·l–1). Sealed ampoules were placed into boiling water bath.
At definite time intervals individual ampoules were cooled,
opened, the solution was transferred into a cell and its
absorbance was measured at 360 nm. The observed rate
constants were calculated from absorbance-time (A-t)
dependences using commercially available software and
equation kobs·t = –ln(At–Aꢀ).
C
O
R1
Figure 2
In our previous paper [10] we studied the kinetics and
mechanism of base catalyzed cyclization giving analogous
1-methyl-2-(subst.phenyl)quinazoline-4-thiones. Studying
this reaction, we found out [11] that in this case
consecutive desulfurization reaction in methanolic sodium
methoxide at room temperature took place leading to the
corresponding quinazoline-4-one. Similar desulfurization
reaction of 3-methyl-2-(subst.phenyl)quinazoline-4-
thiones proceeds very slowly even at elevated temperature
which is probably connected with different tautomeric
forms of quinazoline-4-thione (1H vs. 3H form).
Sample Experimental.
2-Amino-N-methyl-benzamide.
Conclusion.
A 250-ml flask was charged with 10g (0.006 mol) of isatoic
anhydride and 100 ml of water. The mixture was cooled to 2 °C
and 60 ml of 20% aqueous solution of methylamine was added
dropwise during 0.5 h and stirred for another 1 h at 2 °C. Excess
of methylamine and 70 ml of water was removed under vacuum
and separated light brown crystals were collected by filtration
and recrystallized from a mixture of water and ethanol (1:1).
Yield 7.4 g (80%), mp 76-78 °C (in accordance with ref. [13]).
1H nmr (deuteriochloroform): ꢀ 2.84 (dd, 3H, J = 4.8 Hz, J = 0.8
The ring closure reaction of 2-benzoylamino-N-
methylthiobenzamides (1a-f) in the medium of methanolic
sodium methoxide gives good yields of derivatives of 3-
methyl-3-phenylquinazoline-4-thione. In comparison with
the previously studied ring closure reactions of analogous
2-benzoylaminothiobenzamides and 2-[(N-methyl-N-
benzoyl)amino]thiobenzamides, this reaction is much

1284
J.Hanusek, P. Rosa, P. Drabina and M. Sedlák
Vol 43
Hz, CH3), 5.38 (bs, 2H, NH2) 6.54 (t, J = 7.2 Hz , 1H), 6.61 (d,
J = 8.2 Hz, 1H), 7.12 (t, J = 7.3 Hz, 1H), 7.26 (d, J = 7.8 Hz,
1H), 6.51 (bs, 1H, NH). 13C nmr (deuteriochloroform): ꢀ 26.1,
116.0, 116.3, 116.9, 127.0, 131.8, 148.1, 169.9.
Anal. Calcd. for C16H16N2OS: C. 67.58; H. 5.67; N. 9.85; S.
11.27. Found: C. 67.61; H. 5.70; N. 9.40; S. 10.42.
2-Benzoylamino-N-methyl-thiobenzamide (1c).
This compound was obtained as white crystals, yield 62%, mp
194-195 °C; 1H nmr (DMSO-d6): ꢀ 10.86 (bs, 2H , 2ꢀNH), 8.21
(d, J = 8.2 Hz, 1H), 7.96 (d, J = 6.8 Hz, 2H), 7.69-7.59 (m, 3H),
7.51-7.55 (m, 1H), 7.41 (dd, J = 7.7 Hz a 1.45 Hz, 1H), 7.28 (t, J
= 7.5, 1H), 3.18 (s, 3H, NCH3). 13C nmr (DMSO-d6): ꢀ 33.8,
123.7, 125.0, 128.2, 128.2, 129.8, 130.9, 133.0, 134.1, 135.3,
135.9, 165.5, 196.4.
2-Amino-N-methyl-thiobenzamide.
A 250-ml flask was charged with 15 g (0.1 mol) of 2-amino-
N-methyl-benzamide, 22.3 g (0.1 mol) of phosphorus penta-
sulfide, and 70 mL of pyridine. The mixture was refluxed 1.5 h,
whereupon it was cooled and poured onto ice water (250 ml).
The separated yellow crystals of the pyridinium salt of 3-methyl-
2-mercapto-2-thioxo-2,3-dihydro-1H-2ꢁ5-benzo[1.3.2]diazaphos-
phinine-4-thione were collected by filtration and recrystallized
from a mixture of water and dimethylformamide (5:1). Yield 20
g (59%). A 500-ml flask was charged with 20 g (0.06 mol) of
pyridinium salt along with water (70 ml), toluene (70 ml), and
conc. hydrochloric acid (1.3 ml). The reaction mixture was
refluxed until the solid portion completely dissolved and then
continued for next 3 h, whereupon it was cooled to room
temperature, and the separated crystals were collected by
filtration. Yield: 6.3g (64%) yellow crystals, mp 96.5-98.5 °C
(in accordance with ref. [14]). 1H nmr (deuteriochloro-
form): ꢀ 3.15 (dd, 3H, J = 4.8 Hz, J = 0.8 Hz, CH3), 4.93 (bs,
2H, NH2) 6.57 (d, J = 10.8 Hz , 1H), 6.63 (dt, J = 8.3 Hz, J = 1.0
Hz, 1H), 7.01 (dd, J = 9.1 Hz, J = 2.3 Hz, 1H), 7.07 (m, 1H),
8.08 (bs, 1H, NH). 13C nmr (deuteriochloroform): ꢀ 32.9, 117.7,
118.3, 126.8, 127.4, 131.1, 144.9, 200.0.
Anal. Calcd. for C15H14N2OS: C. 66.64; H. 5.22; N. 10.36; S.
11.86. Found: C. 66.36; H. 5.28; N. 10.12; S. 11.66.
2-(4-Chlorbenzoylamino)-N-methyl-thiobenzamide (1d).
This compound was obtained as light yellow crystals, yield
82%, mp 194-196 °C; 1H nmr (DMSO-d6): ꢀ 10.80 (bs, 2H,
2ꢀNH), 8.11 (d, J = 8.2 Hz, 1H), 7.95 (AA´XX´, 2H), 7.69
(AA´XX´, 2H), 7.50-7.55 (m, 1H), 7.41 (d, J = 7.2 Hz, 1H), 7.29
(t, J = 7.5 Hz, 1H), 3.17 (s, 3H, NCH3). 13C nmr (DMSO-
d6): ꢀ 32.8, 123.2, 124.3, 127.3, 128.9, 129.2, 129.9, 133.2,
133.6, 134.7, 136.8, 163.6, 195.4.
Anal. Calcd. for C15H13ClN2OS: C. 59.11; H. 4.30; N. 9.19; S.
10.52; Cl. 11.63. Found: C. 59.46; H. 4.51; N. 9.06; S. 10.35; Cl.
11.86.
2-(4-Nitrobenzoylamino)-N-methyl-thiobenzamide (1e).
This compound was obtained as yellow crystals, yield 66%,
mp 204-206 °C; 1H nmr (DMSO-d6): ꢀ 10.93 (bs, 1H, NH),
10.69 (bs, 1H, NH), 8.44 (AA´XX´, 2H), 8.16 (AA´XX´, 2H),
8.03 (d, J = 7.6 Hz, 1H), 7.54 (t, J = 7.8, 1H), 7.43 (d, J = 7.7,
1H), 7.33 (t, J = 7.5 Hz, 1H), 3.16 (s, 3H, NCH3). 13C nmr
(DMSO-d6): ꢀ 32.9, 123.9, 125.0, 127.6, 124.0, 129.0, 130.0,
134.4, 140.2, 134.6, 149.4, 163.4, 195.6.
General Procedure for Preparation of 2-Benzoylamino-N-
methylthiobenzamides (1a-f).
A 100-ml three-necked flask equipped with a magnetic
stirrer, dropping funnel, and argon inlet was charged with
0.01 mol of 2-amino-N-methyl-thiobenzamide, dry acetone
(35 ml), and 0.01 mol triethylamine. The solution formed
was treated with 0.01 mol of the respective benzoyl chloride
dissolved in acetone (10 ml), added within ca. 5 min. The
reaction mixture was stirred under an argon atmosphere at
Anal. Calcd. for C15H13N3O3S: C. 57.13; H. 4.16; N. 13.33; S.
10.17. Found: C. 57.05; H. 4.13; N. 13.06; S. 10.02.
room temperature
1
h. The separated triethylamine
2-(3-Nitrobenzoylamino)-N-methyl-thiobenzamide (1f).
hydrochloride was collected by filtration, and the filtrate was
evaporated in vacuum at room temperature. Product was
recrystallized from ethanol.
This compound was obtained as light yellow crystals, yield
63%, mp 190-191 °C; 1H nmr (DMSO-d6): ꢀ 10.96 (bs, 1H,
NH), 10.63 (bs, 1H, NH), 8.70 (s, 1H), 8.44 (d, J = 8.2 Hz, 1H),
8.31 (d, J = 7.7 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.86 (t, J = 8.0
Hz, 1H), 7.51-7.47 (m, 1H), 7.40 (d, J = 7.2 Hz, 1H), 7.28 (t, J =
7.5 Hz, 1H), 3.13 (s, 1H, NCH3). 13C nmr (DMSO-d6): ꢀ 33.8,
123.2, 124.9, 125.8, 127.3, 128.5, 130.8, 131.4, 134.5, 135.2,
135.6, 136.9, 148.8, 163.8, 196.6.
2-(4-Methoxybenzoylamino)-N-methyl-thiobenzamide (1a).
This compound was obtained as white crystals, yield 78%,
1
mp 213-215 °C; H nmr (DMSO-d6): ꢀ 10.84 (bs, 1H, NH),
10.72 (bs, 1H, NH), 8.24 (d, J = 7.8 Hz, 1H), 7.93 (AA´XX´,
2H), 7.49-7.54 (m, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.26 (t, J =
7.6 Hz, 1H) 7.15 (AA´XX´, 2H), 3.88 (s, 3H, OCH3), 3.19 (s,
3H, NCH3). 13C nmr (DMSO-d6): ꢀ 33.8, 56.4, 115.0, 123.4,
124.7, 127.3, 128.2, 130.1, 130.9, 133.7, 136.2, 163.2, 164.9,
196.4.
Anal. Calcd. for C15H13N3O3S: C. 57.13; H. 4.16; N. 13.33; S.
10.17. Found: C. 57.45; H. 4.25; N. 12.97; S. 9.92.
General Procedure for preparation of 2-phenyl-3-methyl-
quinazoline-4-thiones (2a-f).
Anal. Calcd. for C16H16N2O2S: C. 63.98; H. 5.37; N. 9.33; S.
10.67. Found: C. 64.08; H. 5.43; N. 9.19; S. 10.48.
A 100-ml flask was charged with 0.02 mol of the respective
thioamide 1a-f and methanol (50 ml). The solution formed was
treated with 1 mol·l–1 sodium methoxide (1 ml), and the reaction
mixture was refluxed 2 h, whereupon it was neutralized with acetic
acid to pH ~ 7 and concentrated to crystallization. The crystalline
product obtained on cooling was recrystallized from ethanol.
2-(4-Methylbenzoylamino)-N-methyl-thiobenzamide (1b).
This compound was obtained as white crystals, yield 82%, mp
1
218-220 °C; H nmr (DMSO-d6): ꢀ 10.88 (bs, 1H, NH), 10.73
(bs, 1H, NH), 8.24 (d, J = 8.1 Hz, 1H), 7.86 (AA´XX´, 2H),
7.50-7.54 (m, 1H), 7.40-7.42 (m, 3H), 7.27 (t, J = 7.6 Hz, 1H),
3.19 (s, 3H, NCH3), 2.43 (s, 3H, CH3). 13C nmr (DMSO-d6): ꢀ
21.1, 32.9, 122.6, 124.0, 127.3, 127.3, 129.4, 130.1, 131.6,
132.9, 135.2, 142.2, 164.5, 195.5.
2-(4-Methoxyphenyl)-3-methylquinazoline-4-thione (2a).
This compound was obtained as yellow crystals, yield 53%,
mp 142-144 °C (ref. [15] gives mp. 147 °C) 1H nmr (DMSO-d6): ꢀ

Sep-Oct 2006
Cyclization of 2-benzoylamino-N-methyl-thiobenzamides
to 2-Phenyl-3-Methyl-3H-quinazolin-4-thiones
1285
2-(3-Nitrophenyl)-3-methylquinazoline-4-thione (2f).
8.72 (d, J = 8.3 Hz, 1H), 7.93 (t, J = 8.2 Hz, 1H), 7.77 (d, J = 8.2
Hz, 1H), 7.73 (AA´XX´, 2H), 7.66 (t, J = 8.2 Hz, 1H), 7.15
(AA´XX´, 2H), 3.90 (s, 3H), 3.89 (s, 3H). 13C nmr (DMSO-
d6): ꢀ 43.2, 55.5, 113.9, 127.9, 128.0, 128.1, 128.3, 130.2, 130.3,
134.8, 142.3, 155.1, 160.5, 188.3.
This compound was obtained as yellow crystals, yield 57%,
1
mp 203-206 °C; H nmr (DMSO-d6): ꢀ 8.77 (d, J = 7.8, 1H),
8.68 (s, 1H), 8.47 (dd, J = 8.3 Hz and 2.3 Hz, 1H), 8.26 (d, J =
7.7 Hz, 1H), 7.97 (t, J = 7.6 Hz, 1H), 7.92 (t, J = 8.0 Hz, 1H),
7.82 (d, J = 8.1 Hz, 1H), 7.72 (m, 1H), 3.85 (s, 3H, NCH3). 13C
nmr (DMSO-d6): ꢀ 42.7, 123.7, 127.7, 128.1, 128.3, 128.8,
130.3, 130.3, 134.9, 135.0, 137.2, 142.0, 147.8, 153.3, 188.1.
Anal. Calcd. for C15H11N3O2S: C. 60.59; H. 3.73; N. 14.13; S.
10.78. Found: C. 60.40; H. 3.67; N. 14.08; S. 10.96.
Anal. Calcd. for C16H14N2OS: C. 68.06; H. 5.00; N. 9.92; S.
11.35. Found: C. 68.32; H. 5.10; N. 9.99; S. 11.53.
2-(4-Methylphenyl)-3-methylquinazoline-4-thione (2b).
This compound was obtained as yellow crystals, yield 53%,
mp 153-155 °C; 1H nmr (DMSO-d6): ꢀ 8.73 (d, J = 8.0 Hz, 1H),
7.94 (t, J = 7.62, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.65-7.70 (m,
3H), 7.42 (AA´XX´, 2H), 3.86 (s, 3H, NCH3), 2.46 (s, 3H, CH3).
13C nmr (DMSO-d6): ꢀ 21.0, 43.0, 127.9, 128.0, 128.4, 129.0,
130.2, 133.0, 134.8, 139.7, 142.2, 145.4, 155.2, 188.1.
Acknowledgement.
This work was supported by the Ministry of Education, Youth
and Sports of the Czech Republic (project No. MSM 002 162
7501).
Anal. Calcd. for C16H14N2S: C. 72.15; H. 5.30; N. 10.52; S.
12.04. Found: C. 71.89; H. 5.20; N. 10.23; S. 12.68.
REFERENCES
2-Phenyl-3-methylquinazoline-4-thione (2c).
[1] A. H. Amin, D. R. Mehta and S. S. Samarth, Fortsch.
Arzneimittelforsch., 14, 218 (1970).
[2] M. W. Partridge and K. J. Butler, J. Chem. Soc., 2396 (1959).
[3] B. Gardner, A. J. S. Kanagasooriam, R. M. Smyth and A.
Williams, J. Org. Chem., 59, 6245 (1994).
[4] P. F. Juby and T. W. Hudyma, (Bristol-Meyers Co.) U.S. 4,
079, 057; Chem. Abstr., 89, 24358m (1978).
[5] S. A. Shiba, A. A. El-Khamry, M. E. Shaban and K. S. Atia,
Pharmazie 52, 189 (1997).
[6] J. M. Hearn, R. A. Morton and J. C. E. Simpson, J. Chem.
Soc., 3318 (1951).
[7] V. Segarra, M. I. Crespo, F. Pujol, J. Beleta, T. Domenech,
M. Miralpeix, J. M. Palacios and A. Castro, Bioorg. Med. Chem. Lett., 8,
505 (1998).
[8] H. M. Blatter and H. Lukaszewski, Tetrahedron Lett., 855
(1964).
[9] J. Hanusek, L. Hejtmánková, L. Kubicová and M. Sedlák,
Molecules, 6, 323 (2001).
[10] J. Hanusek, M. Sedlák, P. ꢀimꢁnek and V. ꢀtꢂrba, Eur. J.
Org. Chem., 1855 (2002).
[11] J. Hanusek, M. Sedlák, R. Keder and V. ꢀtꢂrba: Collect.
Czech. Chem. Commun., 69, 2212 (2004).
[12] D. D. Perrin, In: Dissociation Constants of Organic Bases in
Aqueous Solution, London, Butterworths, 1965.
[13] S. Hayao , H. J. Havera, W. G. Strycker, T. J. Leipzig, R. A.
Kupl and H. G. Hartzler, J. Med. Chem., 8, 807 (1965).
[14] Y. Naito, F. Akahoski, S. Takeda, T. Okada and M. Kajii, J.
Med. Chem., 39, 3019 (1996).
This compound was obtained as yellow crystals, yield 60%,
1
mp 133-135 °C (ref. [16] gives mp. 149 °C); H nmr (DMSO-
d6): ꢀ 8.74 (d, J = 8.3 Hz, 1H), 7.92-7.97 (m, 1H), 7.75-7.79 (m,
3H), 7.68 (t, J = 7.7 Hz, 1H), 7.60-7.63 (m, 3H), 3.85 (s, 3H,
NCH3). 13C nmr (DMSO-d6): ꢀ 43.8, 128.9, 128.9, 129.2, 129.3,
129.4, 130.8, 131.0, 135.6, 136.7, 143.0, 156.0, 188.9.
Anal. Calcd. for C15H12N2S: C. 71.40; H. 4.79; N. 11.10; S.
12.71. Found: C. 71.15; H. 4.95; N. 10.91; S. 12.99.
2-(4-Chlorphenyl)-3-methylquinazoline-4-thione (2d).
This compound was obtained as yellow crystals, yield 59%,
mp 171-173 °C; 1H nmr (DMSO-d6): ꢀ 8.74 (d, J = 8.3 Hz, 1H),
7.95 (t, J = 8.3 Hz, 1H), 7.82 (AA´XX´, 2H), 7.79 (d, J = 8.1 Hz,
1H), 7.66-7.71 (m, 3H), 3.84 (s, 3H, NCH3). 13C nmr (DMSO-
d6): ꢀ 43.7, 129.0, 129.1, 129.5, 129.6, 131.1, 131.4, 135.5,
135.7, 135.7, 143.0, 155.1, 189.0.
Anal. Calcd. for C15H11ClN2S: C. 62.82; H. 3.87; N. 9.77; S. 11.18;
Cl. 12.36. Found: C. 63.11; H. 4.01; N. 9.66; S. 11.26; Cl. 11.96.
2-(4-nitrophenyl)-3-methylquinazoline-4-thione (2e).
This compound was obtained as yellow crystals, yield 53%,
mp 215-218 °C; 1H nmr (DMSO-d6): ꢀ 8.77 (d, J = 8.3 Hz), 8.46
(AA´XX´, 2H), 8.09 (AA´XX´, 2H), 7.98 (t, J = 7.6 Hz, 1H),
7.81 (d, J = 8.2 Hz, 1H), 7.73 (t, J = 7.7 Hz, 1H), 3.83 (s, 3H,
NCH3). 13C nmr (DMSO-d6): ꢀ 42.7, 123.8, 128.2, 128.3, 128.9,
130.2, 130.2, 135.0, 141.6, 142.0, 148.2, 153.6, 188.0.
[15] C. Denis-Garez, L. Legrand and N. Lozac´h, Bull. Soc. Chim.
Fr., 3727 (1969).
Anal. Calcd. for C15H11N3O2S: C. 60.59; H. 3.73; N. 14.13; S.
10.78. Found: C. 60.20; H. 3.70; N. 13.86; S. 11.10.
[16] L. Legrand and N. Lozac´h, Bull. Soc. Chim. Fr., 2090
(1960).