3-Hydroxy- and 3-alkoxy-2-sulfanylquinazolin-4(3H)-ones: Synthesis and reactions with alkylating and acylating agents

Article abstract of DOI:10.1007/s11172-011-0022-1

Reactions of methyl 2-isothiocyanatobenzoate with hydroxylamine and alkoxyamines afforded earlier unknown 3-hydroxy-2-sulfanylquinazolin-4(3H)-one (1a) and 3-alkoxy-2-sulfanylquinazolin-4(3H)-ones (1b,c). Base-catalyzed reactions of compound 1a with alkyl

Full text of DOI:10.1007/s11172-011-0022-1

Russian Chemical Bulletin, International Edition, Vol. 60, No. 1, pp. 153—156, January, 2011
153
3ꢀHydroxyꢀ and 3ꢀalkoxyꢀ2ꢀsulfanylquinazolinꢀ4(3H)ꢀones:
synthesis and reactions with alkylating and acylating agents
P. S. Khokhlov,a V. N. Osipov,b and A. V. Roshchina
aN. N. Semenov Institute of Chemical Physics, Russian Academy of Sciences,
4 ul. Kosygina, 119991 Moscow, Russian Federation.
Fax: +7 (495) 651 2191. Eꢀmail: pskhokh@chhp.ras.ru
bN. N. Blokhin Cancer Research Center, Russian Academy of Medical Sciences,
24 Kashirskoe sh., 115446 Moscow, Russian Federation.
Eꢀmail: ovn@front.ru
Reactions of methyl 2ꢀisothiocyanatobenzoate with hydroxylamine and alkoxyamines
afforded earlier unknown 3ꢀhydroxyꢀ2ꢀsulfanylquinazolinꢀ4(3H)ꢀone (1a) and 3ꢀalkoxyꢀ2ꢀ
sulfanylquinazolinꢀ4(3H)ꢀones (1b,c). Baseꢀcatalyzed reactions of compound 1a with alkyl
halides were not regioselective, yielding O,Sꢀdialkylation products. In the presence of acetic
acid and sodium acetate, compound 1a was alkylated only at the S atom to give 2ꢀalkylsulfanylꢀ
3ꢀhydroxyquinazolinꢀ4(3H)ꢀones. Selective Oꢀacylation of compound 1a at position 3 yielded
3ꢀacyloxyꢀ2ꢀsulfanylquinazolinꢀ4(3H)ꢀones.
Key words: quinazolinones, 2ꢀisothiocyanatobenzoate, hydroxylamines, cyclocondensaꢀ
tion, alkylation, acylation.
Quinazoline fragments are found in many natural alꢀ
kaloids,1,2 biologically active compounds, and drugs.3,4
Among quinazolines, 3ꢀhydroxyquinazolinꢀ4(3H)ꢀone
derivatives constitute an interesting and promising class of
compounds with various types of biological activity,5—9
which can serve as synthons for the synthesis of novel
biologically active compounds through modification of
their OH function.
In the present work, we studied the properties of
3ꢀhydroxyꢀ2ꢀsulfanylquinazolinꢀ4(3H)ꢀone (1a) in search
of methods for selective alkylation of two functional (hydrꢀ
oxy and sulfanyl) groups present in this structure.
Using a procedure involving reactions of methyl 2ꢀisoꢀ
thiocyanatobenzoate with hydroxylamine and alkoxyꢀ
amines,5 we obtained earlier unknown 3ꢀhydroxyꢀ and
3ꢀalkoxyꢀ2ꢀsulfanylquinazolinꢀ4(3H)ꢀones 1a—d.
groups, we alkylated compound 1a with alkyl halides under
different conditions. It is known that baseꢀcatalyzed alkyꢀ
lation of 2ꢀthioxoquinazolinꢀ4ꢀone is regioselective (the
S atom is alkylated only10,11), while its closest analog thioꢀ
uracil is alkylated randomly at the S, O, and N atoms.12
We found that compound 1a in acetic acid in the presꢀ
ence of sodium acetate is alkylated selectively at the S atom
to give 2ꢀalkylsulfanylꢀ3ꢀhydroxyquinazolinꢀ4(3H)ꢀ
ones 2a—e.
Scheme 2
Scheme 1
K2CO3
2: R = Et (a), Allyl (b), Pri (c), CH2C(O)NH2 (d), 2,4ꢀCl ꢀBn (e)
2
1: R = H (a), Me (b), Pri (c), Bui (d)
3: R = Me (a), Prn (b), Bui (c), Bn (d), 2,4ꢀCl ꢀBn (e)
2
With the aim of obtaining derivatives both identically
and differently substituted at the hydroxy and sulfanyl
Baseꢀcatalyzed alkylation of compound 1a occurs at
both the O and S atoms to yield 2,3ꢀdialkylation products,
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 146—149, January, 2011.
1066ꢀ5285/11/6001ꢀ153 © 2011 Springer Science+Business Media, Inc.

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Khokhlov et al.
namely, 3ꢀalkoxyꢀ2ꢀalkylsulfanylquinazolinꢀ4(3H)ꢀones
3a—e, regardless of the ratio of the starting reagents or the
nature of the alkylating agents. With equal amounts (equivꢀ
alents) of compound 1a and alkyl halides, we also obꢀ
tained products 3a—e (<50% yields) and recovered unreꢀ
acted compound 1a; Sꢀmonoalkylated derivatives 2a—e
were not detected in the reaction mixture.
To sum up, we obtained first representatives of earlier
unknown 3ꢀhydroxyꢀ and 3ꢀalkoxyꢀ2ꢀsulfanylquinazolinꢀ
4(3H)ꢀones and developed a method for regioselective
Sꢀalkylation of 3ꢀhydroxyꢀ2ꢀsulfanylquinazolinꢀ4(3H)ꢀone.
Experimental
Asymmetric 3ꢀalkoxyꢀ2ꢀalkylsulfanylquinazolinꢀ4(3H)ꢀ
ones 4a,b were obtained by baseꢀcatalyzed alkylation of
compounds 1b and 2a,b.
1
H NMR spectra were recorded on Bruker ACꢀ300 and Brukꢀ
er WMꢀ250 spectrometers (300 and 250 MHz, respectively) in
DMSOꢀd6. Chemical shifts are given on the δ scale. Mass specꢀ
tra were measured on a Kratos MSꢀ30 instrument (70 eV).
3ꢀHydroxyꢀ2ꢀsulfanylquinazolinꢀ4(3H)ꢀone (1a). A solution
of methyl 2ꢀisothiocyanatobenzoate (19.3 g, 0.1 mol) in chloroꢀ
form (40 mL) was added at 5—10 °C to a stirred solution of
NH2OH•HCl (6.95 g, 0.1 mol) and NaOH (4.0 g, 0.1 mol) in
water (200 mL). The reaction mixture was stirred at room temꢀ
perature for 2 h. The precipitate that formed was filtered off,
washed with water (100 mL) and CH2Cl2 (100 mL), and dried
at 90 °C. The yield was 17.5 g (90%), white crystals, m.p.
252—254 °C (from ethanol). Found (%): C, 49.56; H, 3.10;
N, 14.49; S, 16.49. C8H6N2O2S. Calculated (%): C, 49.48;
Scheme 3
1
H, 3.11; N, 14.42; S, 16.51. H NMR, δ: 7.22 (m, 1 H, H(6));
7.40 (d, 1 H, H(8), J = 7.45 Hz); 7.65 (m, 1 H, H(7)); 8.0 (d, 1 H,
H(5), J = 7.64 Hz); 10.80 (s, 1 H, SH); 12.75 (s, 1 H, OH). MS,
m/z: 194 [M]+.
3ꢀMethoxyꢀ2ꢀsulfanylquinazolinꢀ4(3H)ꢀone (1b). Methyl
2ꢀisothiocyanatobenzoate (19.3 g, 0.1 mol) was added to a stirred
mixture of methoxyamine hydrochloride (8.35 g, 0.1 mol) and
NaOH (4.0 g, 0.1 mol) in dioxane (50 mL) and water (50 mL).
The reaction mixture was stirred at 20—25 °C for 2 h and the
precipitate that formed was filtered off. Yield 19.0 g (89%), white
crystals, m.p. 245—246 °C (from acetone). Found (%): C, 52.05;
H, 3.50; N, 14.00; S, 15.24. C9H8N2O2S. Calculated (%):
C, 51.91; H, 3.87; N, 13.45; S, 15.40. 1H NMR, δ: 4.0 (s, 3 H, Me);
7.35 (d, 1 H, H(6), J = 8.40 Hz); 7.53 (d, 1 H, H(8), J = 7.86 Hz);
7.71 (t, 1 H, H(7), J = 8.16 Hz); 8.21 (d, 1 H, H(5), J = 7.84 Hz);
13.0 (s, 1 H, SH). MS, m/z: 208 [M]+.
Compound 1a was selectively acylated at the OH group
to give 3ꢀacyloxyꢀ2ꢀsulfanylquinazolinꢀ4(3H)ꢀones 5a,b.
Scheme 4
3ꢀIsopropoxyꢀ2ꢀsulfanylquinazolinꢀ4(3H)ꢀone (1c) was obꢀ
tained from isopropoxyamine (7.5 g, 0.1 mol) and methyl
2ꢀisothiocyanatobenzoate (19.3 g, 0.1 mol) as described for comꢀ
pound 1b. Yield 18.0 g (76.4%), white crystals, m.p. 202—204 °C
(from ethanol). Found (%): C, 55.80; H, 5.60; N, 12.20; S, 13.03.
C11H12N2O2S. Calculated (%): C, 55.91; H, 5.12; N, 11.86;
S, 13.56. 1H NMR, δ: 1.35 (d, 6 H, Me, J = 5.5 Hz); 4.85
(m, 1 H, CH); 7.40 (d, 1 H, H(6), J = 8.40 Hz); 7.55 (d, 1 H,
H(8), J = 7.86 Hz); 7.75 (t, 1 H, H(7), J = 8.16 Hz); 8.10
(d, 1 H, H(5), J = 7.84 Hz). MS, m/z: 236 [M]+.
3ꢀIsobutoxyꢀ2ꢀsulfanylquinazolinꢀ4(3H)ꢀone (1d) was obꢀ
tained from isobutoxyamine (4.5 g, 0.05 mol) and methyl
2ꢀisothiocyanatobenzoate (9.65 g, 0.05 mol) as described for comꢀ
pound 1b. Yield 10.6 g (85%), m.p. 210—212 °C (from ethanol).
Found (%): C, 57.11; H, 5.82; N, 11.10; S, 12.34. C12H14N2O2S.
Calculated (%): C, 57.60; H, 5.60; N, 11.20; S, 12.80. 1H NMR,
δ: 1.12 (d, 6 H, Me, J = 6.73 Hz); 2.09 (m, 1 H, CH); 4.10
(d, 2 H, OCH2, J = 6.42 Hz); 7.40 (m, 1 H, H(6)); 7.55 (d, 1 H,
H(8), J = 7.86 Hz); 7.70 (m, 1 H, H(7)); 8.15 (d, 1 H, H(5),
J = 7.84 Hz). MS, m/z: 250 [M]+.
Baseꢀcatalyzed alkylation of compound 5a selectively
yielded 3ꢀacetoxyꢀ2ꢀethylsulfanylquinazolinꢀ4(3H)ꢀone
(6), which can be converted into compound 2a by aminolꢀ
ysis with ammonia in aqueous ethanol.
2ꢀEthylsulfanylꢀ3ꢀhydroxyquinazolinꢀ4(3H)ꢀone (2a). Sodiꢀ
um acetate (1.64 g, 0.02 mol) was added to a solution of comꢀ
pound 1a (3.88 g, 0.02 mol) and ethyl iodide (3.43 g, 0.022 mol)

3ꢀHydroxy(alkoxy)ꢀ2ꢀsulfanylquinazolinꢀ4(3H)ꢀones Russ.Chem.Bull., Int.Ed., Vol. 60, No. 1, January, 2011
155
in acetic acid (20 mL). The reaction mixture was stirred for 1 h
and diluted with water (50 mL). The crystals that formed were
filtered off and dried in air. The yield was 3.57 g (80.3%), m.p.
169—171 °C (from ethanol). Found (%): C, 54.40; H, 4.32;
N, 12.36; S, 14.40. C10H10N2,O2,S. Calculated (%): C, 54.05;
H, 4.53; N, 12.60; S, 14.43. 1H NMR, δ: 1.41 (t, 3 H, Me,
J = 7.17 Hz); 2.92 (m, 2 H, SCH2); 7.31 (t, 1 H, H(6), J = 7.74 Hz);
7.49 (d, 1 H, H(8), J = 8.02 Hz); 7.63 (t, 1 H, H(7), J = 7.95
Hz); 8.00 (d, 1 H, H(5), J = 7.74 Hz); 12.10 (s, 1 H, OH).
Aminolysis of compound 6. Ethanol (5 mL), water (5 mL),
and aqueous ammonia (2 mL) were added to compound 6 (0.82 g,
3 mmol). The reaction mixture was heated at 60 °C for 2 h,
cooled, diluted with water (10 mL), and acidified with 5% HCl
to pH 5. The crystals that formed were filtered off and washed
with water on the filter. The yield was 0.58 g (89%), white crysꢀ
tals, m.p. 170—171 °C (from ethanol). The physicochemical and
spectroscopic characteristics of the product are identical with
those cited above for compound 2a.
7.74 (d, 1 H, H(7), J = 8.90 Hz); 8.02 (d, 1 H, H(5), J = 7.92 Hz);
12.14 (s, 1 H, OH).
3ꢀMethoxyꢀ2ꢀmethylsulfanylquinazolinꢀ4(3H)ꢀone (3a).
Method A. Potassium carbonate (2.8 g, 0.02 mol) was added to
a solution of compound 1a (1.94 g, 0.01 mol) and methyl iodide
(2.52 g, 0.022 mol) in DMSO (15 mL). The reaction mixture was
stirred at 35—45 °C for 6 h and diluted with water (30 mL). The
precipitate that formed was filtered off. The yield was 1.80 g
(80.5%), m.p. 129—130 °C (from hexane). Found (%): C, 54.11;
H, 4.58; N, 12.40; S, 14.34. C10H10N2O2S. Calculated (%):
C, 54.05; H, 4.50; N, 12.61; S, 14.41. 1H NMR, δ: 2.62 (s, 3 H,
SMe); 4.10 (s, 3 H, OMe); 7.41 (t, 1 H, H(6), J = 8.40 Hz); 7.57
(d, 1 H, H(8), J = 7.80 Hz); 7.75 (t, 1 H, H(7), J = 8.16 Hz);
8.10 (d, 1 H, H(5), J = 7.86 Hz).
Method B (with an equivalent amount of an alkyl halide).
Potassium carbonate (1.4 g, 0.01 mol) was added to a solution of
compound 1a (1.94 g, 0.01 mol) and methyl iodide (1.42 g,
0.01 mol) in DMSO (15 mL). The reaction mixture was stirred
at 35—45 °C for 6 h and diluted with water (30 mL). The precipꢀ
itate that formed was filtered off and washed with water. The
yield was 0.91 g (40.8%). The physicochemical and spectroscopꢀ
ic characteristics of the product are identical with those of comꢀ
pound 3a obtained according to method A. The filtrate was acidꢀ
ified with 5% HCl to pH 5. The precipitate that formed was
filtered off and identified from physicochemical and spectroꢀ
scopic data as compound 1a. The yield was 0.88 g (45.3%).
3ꢀPropoxyꢀ2ꢀpropylsulfanylquinazolinꢀ4(H)ꢀone (3b) was obꢀ
tained from compound 1a (1.94 g, 0.01 mol), propyl bromide
(2.46 g, 0.02 mol), and K2CO3 (3.75 g, 0.02 mol) as described for
compound 3a. Yield 2.4 g (86%), m.p. 73—74 °C (from hexane).
Found (%): C, 60.12; H, 6.48; N, 10.03; S 11.50. C14H18N2O2S.
Calculated (%): C, 60.41; H, 6.52; N, 10.06; S, 11.52. 1H NMR,
δ: 1.5 (m, 6 H, Me); 1.82 (m, 2 H, SCH2CH2); 2.03 (m, 2 H,
OCH2CH2); 4.05 (t, 2 H, SCH2, J = 7.07 Hz); 4.90 (t, 2 H,
OCH2, J = 6.86 Hz); 7.35 (t, 1 H, H(6), J = 7.82 Hz); 7.48
(d, 1 H, H(8), J = 8.02 Hz); 7.70 (t, 1 H, H(7), J = 6.98 Hz);
8.10 (d, 1 H, H(5), J = 7.83 Hz).
3ꢀIsobutoxyꢀ2ꢀisobutylsulfanylquinazolinꢀ4(3H)ꢀone (3c).
Potassium carbonate (3.01 g, 0.022 mol) and isobutyl bromide
(3.04 g, 0.022 mol) were added to a stirred solution of compound
1a (1.94 g, 0.01 mol) in DMSO (15 mL). The reaction mixture
was kept at room temperature for 24 h and then diluted with
water (30 mL). The product was extracted with ethyl acetate.
The organic phase was washed with brine (20 mL), dried over
Na2SO4, and concentrated. The yield was 2.26 g (74%), light
yellow oil. Found (%): C, 62.60; H, 7.19; N, 9.40; S, 10.14.
C16H22N2O2S. Calculated (%): C, 62.72; H, 7.24; N, 9.15;
S, 10.46. 1H NMR, δ: 1.03 (d, 12 H, Me, J = 6.72 Hz); 1.97
(m, 1 H, CH); 2.09 (m, 1 H, CH); 3.09 (d, 2 H, SCH2, J = 6.67 Hz);
4.04 (d, 2 H, OCH2, J = 6.42 Hz); 7.32 (d, 1 H, H(6), J = 7.54 Hz);
7.48 (d, 1 H, H(8), J = 8.11 Hz); 7.53 (d, 1 H, H(7), J = 7.68 Hz);
7.98 (d, 1 H, H(5), J = 7.92 Hz).
3ꢀBenzyloxyꢀ2ꢀbenzylsulfanylquinazolinꢀ4(3H)ꢀone (3d) was
obtained from compound 1a (0.01 mol), benzyl bromide (0.02 mol),
and K2CO3 (0.02 mol) as described for compound 3a. Yield
3.37 g (90.0%), m.p. 161—162 °C (from cyclohexane). Found (%):
C, 70.54; H, 4.58; N, 7.40; S, 8.19. C22H18N2O2S. Calculatꢀ
ed (%): C, 70.58; H, 4.81; N, 7.48; S, 8.56. 1H NMR, δ: 4.45
(s, 2 H, SCH2); 5.40 (s, 2 H, OCH2); 7.40 (m, 11 H); 7.67
(d, 1 H, H(8), J = 8.02 Hz); 7.75 (t, 1 H, H(7), J = 6.96 Hz);
8.15 (d, 1 H, H(5), J = 7.84 Hz).
2ꢀAllylsulfanylꢀ3ꢀhydroxyquinazolinꢀ4(3H)ꢀone (2b). Sodium
acetate (0.85 g, 10 mmol) and allyl iodide (1.04 g, 6.2 mmol)
were added to a suspension of compound 1a (1 g, 5.2 mmol) in
a mixture of ethanol (5 mL) and glacial acetic acid (5 mL). The
reaction mixture was refluxed for 3 h. The ethanol was removed
and the residue was diluted with water (20 mL). The crystals that
formed were filtered off, washed with water, and dried in air.
The yield was 0.76 g (63%), m.p. 155—156 °C (from ethyl
acetate). Found (%): C, 56.90; H, 4.28; N, 12.50; S, 13.76.
C11H10N2O2S. Calculated (%): C, 56.40; H, 4.30; N, 11.96;
1
S, 13.69. H NMR, δ: 3.86 (d, 2 H, SCH2, J = 6.79 Hz); 5.15
(d, 2 H, CH2, J = 9.86 Hz); 5.39 (d, 1 H, CH2, J = 17.94 Hz);
5.98 (m, 1 H, CH); 7.41 (d, 1 H, H(6), J = 7.54 Hz); 7.60
(d, 1 H, H(8), J = 7.90 Hz); 7.79 (t, 1 H, H(7), J = 7.62 Hz);
8.10 (d, 1 H, H(5), J = 7.86 Hz); 11.80 (s, 1 H, OH).
3ꢀHydroxyꢀ2ꢀisopropylsulfanylquinazolinꢀ4(3H)ꢀone (2c) was
obtained from compound 1a (1 g, 5.2 mmol) and isopropyl
iodide (1.05 g, 6.2 mmol) as described above for compound 2b.
Yield 1.1 g (90%), white crystals, m.p. 190—191 °C (from ethyl
acetate). Found (%): C, 56.34; H, 5.15; N, 12.21; S, 13.18.
C11H11N2O2S. Calculated (%): C, 56.91; H, 5.12; N, 11.86;
S, 13.57. 1H NMR, δ: 1.43 (d, 6 H, Me, J = 6.85 Hz); 3.92 (m, 1 H,
CH); 7.43 (d, 1 H, H(6), J = 7.83 Hz); 7.58 (d, 1 H, H(8),
J = 8.01 Hz); 7.81 (d, 1 H, H(7), J = 6.96 Hz); 8.19 (d, 1 H,
H(5), J = 7.83 Hz); 11.21 (s, 1 H, OH).
2ꢀCarbamoylmethylsulfanylꢀ3ꢀhydroxyquinazolinꢀ4(3H)ꢀone
(2d) was obtained from compound 1a (1 g, 5.2 mmol) and chloroꢀ
acetamide (0.56 g, 6 mmol) as described for compound 2b. Yield
1.08 g (83%), white crystals, m.p. 218—220 °C (from ethanol).
Found (%): C, 47.85; H, 3.48; N, 16.66; S, 12.70. C10H9N3O3S.
Calculated (%): C, 47.80; H, 3.61; N, 16.72; S, 12.76. 1H NMR,
δ: 3.85 (s, 2 H, CH2); 7.45 (d, 1 H, H(6), J = 7.82 Hz); 7.50 (br.s,
2 H, NH2); 7.60 (d, 1 H, H(8), J = 8.02 Hz); 7.77 (d, 1 H, H(7),
J = 6.98 Hz); 8.10 (d, 1 H, H(5), J = 7.88 Hz); 11.82 (s, 1 H, OH).
2ꢀ(2,4ꢀDichlorobenzyl)sulfanylꢀ3ꢀhydroxyquinazolinꢀ4(3H)ꢀ
one (2e) was obtained from compound 1a (1 g, 5.2 mmol) and
2,4ꢀdichlorobenzyl chloride (1.07 g, 5.5 mmol) as described
for compound 2b. Yield 1.69 g (92%), white crystals, m.p.
225—226 °C (from ethanol). Found (%): C, 51.18; Cl, 19.80;
H, 2.88; N, 7.75; S, 9.38. C15H10Cl2N2O2S. Calculated (%):
C, 51.01; Cl, 20.07; H, 2.85; N, 7.93; S, 9.08. 1H NMR, δ: 4.38
(s, 2 H, SCH2); 7.31 (d, 1 H, H(6), J = 7.83 Hz); 7.40 (d, 1 H,
H(8), J = 8.43 Hz); 7.59 (s, 1 H, Ar); 7.65 (d, 2 H, Ar, J = 7.52 Hz);

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Khokhlov et al.
3ꢀ(2,4ꢀDichlorobenzyloxy)ꢀ2ꢀ(2,4ꢀdichlorobenzylsulfanyl)ꢀ
reaction mixture was refluxed for 3 h and cooled. The crystals
that formed were filtered off and washed with ether. The yield was
0.54 g (77%), m.p. 215—216 °C (from ethyl acetate). Found (%):
C, 44.40; Cl, 13.30; H, 2.55, N, 10.44; S, 11.80. C10H7ClN2O3S.
Calculated (%): C, 44.36; Cl, 13.10; H, 2.61; N, 10.35; S, 11.82.
1H NMR, δ: 4.94 (s, 2 H, CH2); 7.51 (m, 1 H, H(6)); 7.56
(d, 1 H, H(8), J = 8.04 Hz); 7.86 (t, 1 H, H(7), J = 7.94 Hz);
8.02 (d, 1 H, H(5), J = 6.81 Hz); 13.42 (s, 1 H, SH).
3ꢀAcetoxyꢀ2ꢀethylsulfanylquinazolinꢀ4(3H)ꢀone (6). Potassiꢀ
um carbonate (0.65 g, 4.7 mmol) and ethyl bromide (0.51 g,
4.7 mmol) were added to a stirred solution of compound 5a (1 g,
4.2 mmol) in DMSO (7 mL). The reaction mixture was kept at
room temperature for ~8 h and diluted with water (10 mL). The
oil that formed was subjected to extraction with ethyl acetate
(2×10 mL). The organic layer was washed with water (10 mL)
and brine (10 mL), dried over Na2SO4, and concentrated. The
yield was 0.82 g (74%), light oil. Found (%): C, 54.23; H, 4.52;
N, 10.80; S, 11.95. C12H12N2O3S. Calculated (%): C, 54.53;
H, 4.58; N, 10.60; S, 12.13. 1H NMR, δ: 1.38 (t, 3 H, Me,
J = 7.82 Hz); 2.45 (s, 3 H, C(O)CH3); 3.20 (m, 2 H, SCH2); 7.42
(t, 1 H, H(6), J = 7.83 Hz); 7.58 (d, 1 H, H(8), J = 8.01 Hz);
7.85 (t, 1 H, H(7), J = 7.94 Hz); 8.10 (d, 1 H, H(5), J = 7.80 Hz).
quinazolinꢀ4(3H)ꢀone (3e) was obtained from compound 1a (1.94 g,
0.01 mol), 2,4ꢀdichlorobenzyl chloride (3.91 g, 0.02 mol), and
K2CO3 (2.75 g, 0.02 mol) as described for compound 3a. Yield
4.28 g (84%), white crystals, m.p. 182—183 °C (from cycloꢀ
hexane). Found (%): C, 51.23; Cl, 27.50; H, 2.70; N, 5.80;
S, 6.21. C22H14Cl4N2O2S. Calculated (%): C, 51.59; Cl, 27.70;
H, 2.75; N, 5.47; S, 6.26. 1H NMR, δ: 4.50 (s, 2 H, SCH2); 5.38
(s, 2 H, OCH2); 7.25 (d, 1 H, arom., J = 8.24 Hz); 7.35 (d, 1 H,
arom., J = 8.22 Hz); 7.45 (m, 5 H, arom.); 7.65 (s, 1 H, arom.);
7.78 (t, 1 H, H(7), J = 8.11 Hz); 8.13 (d, 1 H, H(5), J = 7.76 Hz).
2ꢀEthylsulfanylꢀ3ꢀmethoxyquinazolinꢀ4(3H)ꢀone (4a). Methꢀ
od A. Potassium carbonate (1.4 g, 0.01 mol) was added to
a solution of compound 1b (2.08 g, 0.01 mol) and ethyl iodide
(1.56 g, 0.01 mol) in DMSO (15 mL). The reaction mixture was
stirred at 45 °C for 6 h, cooled, and diluted with water (30 mL).
The precipitate that formed was filtered off. The yield was 1.90 g
(80%), beige crystals, m.p. 63—64 °C (from cyclohexane).
Found (%): C, 55.40; H, 5.24; N, 12.00; S, 13.44. C11H12N2O2S.
Calculated (%): C, 55.90; H, 5.08; N, 11.86; S, 13.56. 1H NMR,
δ: 1.38 (t, 3 H, Me); 3.15 (q, 2 H, SCH2); 4.1 (s, 3 H, OMe); 7.12
(d, 1 H, H(6), J = 7.86 Hz); 7.52 (t, 1 H, H(8), J = 8.04 Hz);
7.77 (t, 1 H, H(7), J = 6.98 Hz); 8.12 (d, 1 H, H(5), J = 7.87 Hz).
Method B. Potassium carbonate (1.4 g, 0.01 mol) was added
to a solution of compound 2a (2.22 g, 0.01 mol) and methyl
iodide (1.56 g, 0.011 mol) in DMSO (15 mL). The reaction
mixture was stirred at 45 °C for 6 h, cooled, and diluted with
water (30 mL). The precipitate that formed was filtered off. The
yield was 1.96 g (82.3%). The physicochemical and spectroꢀ
scopic characteristics of the product are identical with those of
compound 4a obtained according to method A.
2ꢀAllylsulfanylꢀ3ꢀmethoxyquinazolinꢀ4(3H)ꢀone (4b). Potasꢀ
sium carbonate (1.4 g, 0.01 mol) was added to a solution of
compound 2b (2.34 g, 0.01 mol) and methyl iodide (1.56 g,
0.011 mol) in DMSO (15 mL). The reaction mixture was stirred
at 45 °C for 6 h, cooled, and diluted with water (30 mL). The
precipitate that formed was filtered off. The yield was 2.10 g
(84.6%), beige crystals, m.p. 134—135 °C (from cyclohexane).
Found (%): C, 57.97; H, 4.85; N, 11.14; S, 12.74. C12H12N2O2S.
Calculated (%): C, 58.06; H, 4.87; N, 11.28; S, 12.91. 1H NMR,
δ: 3.90 (d, 2 H, SCH2, J = 6.79 Hz); 4.1 (s, 3 H, OMe); 5.18
(d, 1 H, CH2, J = 9.88 Hz); 5.38 (d, 1 H, CH2, J = 17.94 Hz);
6.00 (m, 1 H, CH); 7.40 (t, 1 H, H(6), J = 7.45 Hz); 7.55 (d, 1 H,
H(8), J = 8.01 Hz); 7.72 (t, 1 H, H(7), J = 7.62 Hz); 8.12
(d, 1 H, H(5), J = 7.84 Hz).
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3ꢀAcetoxyꢀ2ꢀsulfanylquinazolinꢀ4(3H)ꢀone (5a). Acetyl chloꢀ
ride (1.6 g, 0.02 mol) was added at 10 °C to a stirred solution of
compound 1a (3.9 g, 0.02 mol) and triethylamine (2.0 g, 0.02 mol)
in dioxane (20 mL). The reaction mixture was stirred at room
temperature for 12 h and diluted with water (40 mL). The preꢀ
cipitate that formed was filtered off, dried, and crystallized from
ethyl acetate. The yield was 4.0 g (90%), m.p. 265—266 °C (from
ethyl acetate). Found (%): C, 50.40; H, 3.28; N, 11.60; S, 13.40.
C10H8N2O3S. Calculated (%): C, 50.84; H, 3.41; N, 11.86;
S, 13.56. 1H NMR, δ: 2.45 (s, 3 H, CH3); 7.42 (t, 1 H, H(6),
J = 7.83 Hz); 7.58 (d, 1 H, H(8), J = 8.01 Hz); 7.85 (t, 1 H,
H(7), J = 7.94 Hz); 8.10 (d, 1 H, H(5), J = 6.81 Hz); 13.34
(s, 1 H, SH).
3ꢀChloroacetoxyꢀ2ꢀsulfanylquinazolinꢀ4(3H)ꢀone (5b). Chloroꢀ
acetic anhydride (0.53 g, 3.1 mmol) was added to a suspension of
compound 1a (0.5 g, 2.6 mmol) in chloroform (30 mL). The
Received January 28, 2010;
in revised form October 25, 2010