Synthesis of new sulfonamide derivatives of thiazolo[3,2-a]quinazolin-5-one

Article abstract of DOI:10.1134/S1070428016010139

A general procedure has been proposed for the synthesis of thiazolo[3,2-a]quinazolin-5-one derivatives containing a sulfonamide group on C⁷via intramolecular nucleophilic substitution of halogen in 2-halo-5-sulfamoyl-N-(1,3-thiazol-2-yl)benzami

Full text of DOI:10.1134/S1070428016010139

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2016, Vol. 52, No. 1, pp. 69–75. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © R.M. Shlenev, S.I. Filimonov, A.V. Tarasov, A.S. Danilova, P.A. Agat’ev, 2016, published in Zhurnal Organicheskoi Khimii, 2016,
Vol. 52, No. 1, pp. 76–82.
Synthesis of New Sulfonamide Derivatives
of Thiazolo[3,2-a]quinazolin-5-one
R. M. Shlenev, S. I. Filimonov, A. V. Tarasov, A. S. Danilova, and P. A. Agat’ev
Yaroslavl State Technical University, Moskovskii pr. 88, Yaroslavl, 150023 Russia
e-mail: schlenev.roman@yandex.ru
Received October 9, 2015
Abstract—A general procedure has been proposed for the synthesis of thiazolo[3,2-a]quinazolin-5-one deriv-
atives containing a sulfonamide group on C7 via intramolecular nucleophilic substitution of halogen in 2-halo-
5-sulfamoyl-N-(1,3-thiazol-2-yl)benzamides. The effects of the degree of activation of the initial compound and
halogen nature on the yield of the target products have been analyzed.
DOI: 10.1134/S1070428016010139
The number of studies aimed at developing meth-
ods of synthesis of fused tricyclic quinazoline deriva-
tives has considerably increased in the past two
decades. Potential antitumor and anticancer agents
have been found among these compounds, in particular
thiazolo[2,3-b]quinazolines and thiazolo[2,3-b]quinaz-
olinones [1–3]. It is also known that compounds
containing a thiazolo[2,3-b]quinazolinone fragment are
efficient α1-adrenoceptor antagonists [4]. Not only [b]-
but also [a]-fused quinazolinones attract interest from
the practical viewpoint. Some 1,2,4-triazolo[1,5-a]-
quinazolinones showed pronounced antimicrobial ac-
tivity [5], while pyrido[1,2-a]quinazolin-6-one and
pyrazolo[1,5-a]quinazolin-5-one derivatives were
found to exhibit tuberculostatic activity [6]. Therefore,
apart from thiazolo[2,3-b]quinazolinones, isomeric
thiazolo[3,2-a]quinazolinones may be interesting as
potential biologically active substances.
to develop a general procedure for the synthesis of
sulfonamide derivatives of thiazolo[3,2-a]quinazolin-
5-one. Direct selective chlorosulfonation of thiazolo-
[3,2-a]quinazolin-5-one at one position of the aromatic
or thiazole fragment and subsequent treatment of the
resulting sulfonyl chloride with an amine seemed to be
a difficult task. Therefore, more promising are methods
utilizing building blocks that already possess necessary
functionalities.
Among known catalytic [7–10] and noncatalytic
[11–13] synthetic approaches to the targeted hetero-
cyclic system, the most interesting was that based on
the condensation of substituted 2-halobenzoyl chlo-
rides with 2-aminothiazole [14] (Scheme 1). This
approach implies the use of a substrate containing
an activated halogen substituent in the 2-position. Its
activation may be achieved by introduction of other
substituents with a comparable electron-withdrawing
effect, such as sulfamoyl group.
Thiazolo[3,2-a]quinazolinones containing a sulfon-
amide group directly attached to the cyclic system
have not been reported so far, though such modifica-
tion could enhance their biological activity and im-
prove the solubility. The goal of the present work was
Thus, the scheme of synthesis of sulfonamide
derivatives of thiazolo[3,2-a]quinazolin-5-one will
differ from that described above only in the step of
preparation of intermediate benzamides. A reasonable
Scheme 1.
N
S
O
F
O
F
O
F
N
O
N
NH2
F
F
F
F
F
F
F
F
PhMe, ∆
Ph2O, ∆
S
OH
Cl
N
N
H
S
F
F
F
F
69

SHLENEV et al.
70
Scheme 2.
N
S
O
O
O
N
NH2
ClSO2
R1
ClSO2
R1
ClSO2
R1
SOCl2, DMF, ∆
MeCN, pyridine, 25°C
S
OH
Cl
N
H
Hlg
Hlg
Hlg
1a–1d
2a–2d
3a–3d
O
N
O
N
O
O
O
O
S
S
R2R3NH, MeCN
R2R3N
N
H
R2R3N
N
S
R1
Hlg
R1
S
4a–4l
5a–5f
1–3, Hlg = F, R1 = H (a); Hlg = Cl, R1 = H (b), Cl (c); Hlg = Br, R1 = H (d); 4, Hlg = F, R1 = H (a–c); Hlg = Cl, R1 = H (d–f),
Cl (g–i); Hlg = Br, R1 = H (j–l); R2R3N = morpholin-4-yl (a, d, g, j); R2 = H, R3 = Ph (b, e, h, k); R2R3N = piperidin-1-yl (c, f, i, l);
5, R1 = H (a–c), Cl (d–f); R2R3N = morpholin-4-yl (a, d); R2 = H, R3 = Ph (b, e); R2R3N = piperidin-1-yl (c, f).
scheme includes the synthesis of chlorosulfonyl-sub-
stituted benzoyl chloride 2, acylation of 2-amino-
thiazole, and sulfonation of amines with sulfonyl
chloride 3 in the final step (Scheme 2).
tively (Scheme 3). In the other cases, the initial com-
pounds were recovered from the reaction mixtures
(they were identified by TLC and by the melting
1
points). The H NMR spectra of 5a–5f contained no
signal assignable to CONH proton in the region
δ 13.0–13.5 ppm, and all signals showed downfield
shifts relative those of the initial amides. The structure
It is known that the reactivities of the COCl and
SO2Cl groups in sulfobenzoic acid dichlorides (e.g.,
2a–2d) toward aromatic amines may differ by a factor
of up to 900; therefore, the SO2Cl group can be re-
tained in the acylation products [15, 16]. In fact, by
reaction of 2-aminothiazole with dichlorides 2a–2d we
obtained in all cases the corresponding sulfonyl
chlorides 3a–3d in 46–76% yield. The IR spectra of
3a–3d displayed absorption bands typical of stretching
and bending vibrations of the amide N–H group and
strong absorption bands due to vibrations of SO2Cl
group. Sulfonamides 4a–4l were synthesized in 50–
80% yield by treatment of 3a–3d with excess morpho-
line, aniline, or piperidine in acetonitrile (see Experi-
1
of 5a was additionally confirmed using H–1H and
1H–13C shift correlation techniques. The NOESY spec-
trum of 5a revealed a strong cross-peak between 1-H
and 9-H, whereas its HMBC spectrum showed no
correlation between 1-H and carbonyl carbon atom,
which indicated selective formation of angularly fused
product.
Our attempts to obtain compounds 5a–5c from
amides 4d–4f and 4j–4l at higher temperature (by
replacing DMF by N,N-dimethylacetamide) were un-
successful. We succeeded in isolating fused quinazo-
linones 5a–5c in 23–26% yield (after purification) only
when amides 4d–4f were heated in high-boiling di-
phenyl ether. Amides 4j–4l failed to react even under
such harsh conditions.
1
mental). The H NMR spectra of 4a–4l contained
a signal at δ 13.0–13.5 ppm due to the CONH proton
and characteristic signals from protons in the sulfon-
amide fragment.
Up to now, only a few data have been reported on
intramolecular nucleophilic substitution of halogen in
compounds like 4. Therefore, the substituents in 4a–4l
were intentionally selected so that they constituted
a small model series for the estimation of the effects of
halogen nature and degree of its activation on the
formation of cyclic structure.
The cyclization of amides 4a–4l was carried out
under identical conditions (reaction time, substrate
concentration) in boiling dimethylformamide. Cyclic
products 5a–5c (57–59%) and 5d–5f (50–54%) were
formed only from amides 4a–4c and 4g–4i, respec-
We also found that compound 6, an analog of 4d–4f
containing a slightly more electron-withdrawing ben-
zenesulfonyl substituent instead of sulfamoyl group, is
capable of undergoing intramolecular cyclization on
heating in DMF (i.e., at a temperature lower by 100°C)
to afford 47% of thiazoloquinazolinone 7.
Analysis of the obtained results showed that in the
series 4a–4c, 4d–4f, and 4j–4l the best leaving group
is fluorine atom provided that halogen activation
factors are similar. Comparison of the reactivity of the
chlorine atom in 4d–4f, 6, and 4g–4i revealed a cor-
relation between the electron-withdrawing power of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 1 2016

SYNTHESIS OF NEW SULFONAMIDE DERIVATIVES
71
Scheme 3.
O
F
N
O
N
O
N
O
O
O
O
O
O
S
S
S
R2R3N
N
R2R3N
N
R2R3N
N
S
S
S
H
H
H
Cl
Br
4a–4c
4d–4f
4j–4l
DMF or DMA, ∆
Ph2O, ∆
O
5
O
O
6
S
5a
7
R2R3N
N4
Ph2O, ∆
DMF, ∆
3a
8
10
N
S3
9a
9
H
2
1
NOE
H
5a–5c
O
N
O
N
N
O
O
O
O
S
S
R2R3N
N
H
R2R3N
DMF, ∆
S
Cl
Cl
O
Cl
S
4g–4i
5d–5f
N
O
O
O
O
O
S
S
DMF, ∆
S
Ph
N
H
Ph
N
Cl
N
S
6
7
substituents activating the halogen atom and the rate of
nucleophilic substitution which sharply increases in the
given series.
spectrometer with Fourier transform from samples dis-
persed in mineral oil and placed between KBr plates.
The mass spectra (electron impact, 70 eV) were ob-
tained on a Finnigan MAT Incos 50 mass spectrometer
(ion source temperature 100–220°C).
5-Chlorosulfonyl-2-fluorobenzoyl chloride (2a).
A mixture of 6 g of 5-chlorosulfonyl-2-fluorobenzoic
acid (1a), 10 mL of thionyl chloride, and 2 drops of
DMF was heated under reflux until hydrogen chloride
no longer evolved. Excess thionyl chloride was dis-
tilled off, and the residue was immediately used in the
synthesis of 3a.
The described procedure is applicable to the prepa-
ration of a wide range of thiazolo[3,2-a]quinazolin-
5-one derivatives containing various sulfonamide
fragments, and the obtained results may ensure proper
choice of starting compounds and necessary reaction
conditions. The use of accessible initial compounds
and reaction media and no need of catalyst also make
the proposed procedure advantageous.
Compounds 2b–2d were synthesized in a similar
way.
EXPERIMENTAL
1
The H NMR spectra were recorded on Bruker
4-Fluoro-3-(1,3-thiazol-2-ylcarbamoyl)benzene-
1-sulfonyl chloride (3a). A mixture of 30 mL of aceto-
nitrile, 2.34 g (0.023 mol) of 2-aminothiazole, and
1.88 mL (0.023 mol) of pyridine was added over
a period of 30 min under vigorous stirring at 25°C to
a solution of 6 g (0.023 mol) of compound 2a in 20 mL
DRX-400 (400 MHz) and Bruker DRX-500 spectrom-
eters (500 MHz); the C NMR spectra were measured
on a Bruker DRX-500 instrument (125 MHz);
DMSO-d6 was used as solvent. The IR spectra (700–
4000 cm–1) were registered on a Perkin Elmer RX-1
13
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 1 2016

SHLENEV et al.
(1H, 5′-H, 3J = 3.6 Hz), 7.57 d (1H, 4′-H, 3J = 3.6 Hz),
72
of acetonitrile. The mixture was stirred for 1 h at that
temperature and poured into 200 mL of water. The
product was filtered off, dried, and recrystallized from
toluene. Yield 3.456 g (46%), white crystals, mp 128–
132°C. IR spectrum, ν, cm–1: 3138, 3099 (N–H); 3064
(C–Harom), 1682 (C=O), 1607 (C=Cthiaz), 1572 (δN–H,
C=N), 1185 (SO2Cl). Found, %: C 37.56; H 1.90;
N 8.61; S 20.27. C10H6ClFN2O3S2. Calculated, %:
C 37.45; H 1.89; N 8.73; S 19.99.
3
3
7.67 d.d (1H, 3-H, JHH = J HF = 8.8 Hz), 7.98 d.d.d
3
4
4
(1H, 4-H, JHH = 8.8, J HF = 4.6, J HH = 2.4 Hz),
4
4
8.09 d.d (1H, 6-H, J HF = 6.3, J HH = 2.4 Hz), 12.9 s
(1H, NH). Mass spectrum, m/z (Irel, %): 371 (4) [M]+,
272 (23), 222 (68), 194 (11), 187 (52), 139 (19), 127
(10), 123 (71), 122 (61), 95 (20), 94 (78), 86 (70), 84
(12), 58 (11), 57 (18), 56 (100), 55 (28), 45 (18), 42
(18), 41 (12), 30 (23), 29 (43), 28 (18), 27 (15), 15
(12). Calculated: M 371.41.
Compounds 3b–3d were synthesized in a similar
2-Fluoro-5-(phenylsulfamoyl)-N-(1,3-thiazol-
2-yl)benzamide (4b). Compound 3a, 1 g (3.1 mmol),
was dispersed in 5 mL of acetonitrile, 0.28 mL
(3.1 mmol) of aniline and 0.25 mL (3.1 mmol) of pyri-
dine were added, and the mixture was kept for 3.5 h at
20°C. The mixture was treated with 10 mL of distilled
water and acidified to pH 2–3 with a small amount of
concentrated aqueous HCl. The precipitate was filtered
off and discarded. The filtrate was diluted with 10 mL
of ethanol, the mixture was poured into distilled water,
and the precipitate was filtered off and purified by
recrystallization from glacial acetic acid–acetonitrile–
water (3:3:1 by volume). Yield 0.641 g (54%), light
brown crystals, mp 147–150°C. IR spectrum, ν, cm–1:
3067 (C–Harom), 1664 (C=O), 1613 (C=Cthiaz), 1545
way.
4-Chloro-3-(1,3-thiazol-2-ylcarbamoyl)benzene-
1-sulfonyl chloride (3b). Yield 5.554 g (75%), white
crystals, mp 198–203°C. IR spectrum, ν, cm–1: 3141
(N–H), 3080 (C–Harom), 1703 (C=O), 1571 (δN–H,
C=N), 1177 (SO2Cl). Found, %: C 35.74; H 1.77;
N 8.22; S 18.80. C10H6Cl2N2O3S2. Calculated, %:
C 35.62; H 1.79; N 8.31; S 19.02.
2,4-Dichloro-3-(1,3-thiazol-2-ylcarbamoyl)ben-
zene-1-sulfonyl chloride (3c). Yield 5.485 g (76%),
white crystals, mp 190–194°C. IR spectrum, ν, cm–1:
3167, 3132 (N–H); 3094 (C–Harom); 1669 (C=O); 1582
(C=Carom); 1567, 1535 (δN–H, C=N); 1394, 1182
(SO2Cl). Found, %: C 32.24; H 1.38; N 7.63; S 16.98.
C10H5Cl3N2O3S2. Calculated, %: C 32.32; H 1.36;
N 7.54; S 17.26.
1
(δN–H, C=N), 1345, 1160 (SO2). H NMR spectrum
3
(400 MHz), δ, ppm: 7.06 t (1H, p-H, J = 7.9 Hz),
3
3
7.11 d (2H, o-H, J = 7.9 Hz), 7.25 t (2H, m-H, J =
4-Bromo-3-(1,3-thiazol-2-ylcarbamoyl)benzene-
1-sulfonyl chloride (3d). Yield 5.290 g (73%), light
brown crystals, mp 243°C (decomp.). IR spectrum, ν,
cm–1: 3167, 3123 (N–H); 3068 (C–Harom); 1678 (C=O);
1571, 1559 (δN–H, C=N); 1183 (SO2Cl). Found, %:
C 31.36; H 1.57; N 7.23; S 16.99. C10H6ClBrN2O3S2.
Calculated, %: C 31.47; H 1.60; N 7.34; S 16.80.
3
7.9 Hz), 7.33 d (1H, 5′-H, J = 3.6 Hz), 7.56 m (2H,
9-H, 4′-H), 7.94 d.d.d (1H, 4-H, 3JHH = 8.9, 4J HF = 4.7,
4J HH = 2.4 Hz), 8.13 d.d (1H, 6-H, JHF = 6.2, JHH
=
4
4
2.4 Hz), 10.40 s (1H, SO2NH), 12.70 s (1H, CONH).
Found, %: C 51.03; H 3.22; N 10.98; S 16.72.
C16H12FN3O3S2. Calculated, %: C 50.92; H 3.20;
N 11.13; S 16.99.
2-Fluoro-5-(morpholine-4-sulfonyl)-N-(1,3-thia-
zol-2-yl)benzamide (4a). Compound 3a, 1 g
(3.1 mmol), was dispersed in 5 mL of acetonitrile,
0.27 mL (3.1 mmol) of morpholine and 0.43 mL
(3.1 mmol) of triethylamine were added under vigor-
ous stirring on cooling, and the mixture was stirred for
10 min at room temperature. The mixture was then
treated with 10 mL of water and acidified to pH 2–3
with a small amount of concentrated aqueous HCl. The
precipitate was filtered off and purified by recrystal-
lization from glacial acetic acid–acetonitrile–water
(3:3:1 by volume). Yield 0.675 g (58%), light brown
crystals, mp 193–195°C. IR spectrum, ν, cm–1: 3167,
3132 (N–H); 1662 (C=O); 1610 (C=C); 1580
(C=Carom); 1549 (δN–H, C=N); 1351, 1169 (SO2);
1112, 947 (C–O–C). 1H NMR spectrum (500 MHz), δ,
ppm: 2.95 t (4H, NCH2), 3.65 t (4H, OCH2), 7.34 d
Compounds 4e, 4h, and 4k were synthesized in
a similar way.
2-Fluoro-5-(piperidine-1-sulfonyl)-N-(1,3-thiazol-
2-yl)benzamide (4c) was synthesized as described
above for 4a. Yield 0.658 g (59%), light brown plates,
mp 188–191°C. IR spectrum, ν, cm–1: 3186, 3131
(N–H); 1678 (C=O); 1610 (C=C); 1568 (δN–H, C=N);
1
1481 (C=Carom); 1345, 1163 (SO2). H NMR spectrum
(400 MHz), δ, ppm: 1.32–1.62 m (6H, CH2), 2.94 t
3
(4H, NCH2), 7.34 d (1H, 5′-H, J = 3.6 Hz), 7.57 d
3
3
(1H, 4′-H, J = 3.6 Hz), 7.64 t (1H, 3-H, JHH = 3JHF
=
3
4
9.4 Hz), 7.96 d.d.d (1H, 4-H, JHH = 9.4, J HF = 4.6,
4JHH = 2.4 Hz), 8.07 d.d (1H, 6-H, JHF = 6.4, JHH
=
4
4
2.4 Hz), 12.9 s (1H, NH). Found, %: C 48.62; H 4.43;
N 11.24; S 17.64. C15H16FN3O3S2. Calculated, %:
C 48.77; H 4.37; N 11.37; S 17.36.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 1 2016

SYNTHESIS OF NEW SULFONAMIDE DERIVATIVES
73
2-Chloro-5-(morpholine-4-sulfonyl)-N-(1,3-thia-
zol-2-yl)benzamide (4d). Morpholine, 1.15 mL
(13.2 mmol), was added under vigorous stirring and
cooling to a suspension of 1.5 g (4.4 mmol) of com-
pound 3b in 5 mL of acetonitrile, and the mixture was
stirred for 10 min at room temperature. The mixture
was then treated with 10 mL of water and acidified to
pH 2–3 with a small amount of concentrated aqueous
HCl. The precipitate was filtered off and purified by
recrystallization from glacial acetic acid–acetonitrile–
water (3:3:1 by volume). Yield 1.341 g (78%), white
plates, mp 198–200°C. IR spectrum, ν, cm–1: 3183,
3130 (N–H); 3082 (C–Harom); 1675 (C=O); 1589
(C=Carom, δN–H, C=N); 1356, 1163 (SO2); 1114, 943
4′-H, 3J = 3.6 Hz), 7.85 m (2H, 3-H, 4-H), 7.97 s (1H,
6-H), 12.89 s (1H, NH). Found, %: C 46.58; H 4.22;
N 10.98; S 16.34. C15H16ClN3O3S2. Calculated, %:
C 46.69; H 4.18; N 10.89; S 16.62.
2,4-Dichloro-5-(morpholine-4-sulfonyl)-N-(1,3-
thiazol-2-yl)benzamide (4g) was synthesized from 1 g
of sulfonyl chloride 3c. Yield 0.697 g (61%), light
brown crystals, mp 198–200°C. IR spectrum, ν, cm–1:
3260 (N–H); 1684 (C=O); 1550 (δN–H, C=N); 1315,
1
1158 (SO2); 1112, 953 (C–O–C). H NMR spectrum
(500 MHz), δ, ppm: 3.24 t (4H, NCH2), 3.63 t (4H,
3
OCH2), 7.36 d (1H, 5′-H, J = 3.6 Hz), 7.57 d (1H,
3
4′-H, J = 3.6 Hz), 8.11 s (1H, 3-H), 8.20 s (1H, 6-H),
12.92 s (1H, NH). Mass spectrum, m/z (Irel, %): 421 (2)
[M]+, 388 (6), 386 (19), 326 (9), 325 (5), 324 (46), 323
(7), 322 (71), 276 (10), 275 (7), 274 (65), 273 (13),
272 (100), 246 (14), 244 (21), 239 (21), 237 (30), 189
(15), 175 (9), 174 (31), 173 (20), 172 (49), 146 (23),
145 (16), 144 (36), 109 (16), 86 (35), 84 (39), 56
(82), 55 (24), 45 (13), 42 (13), 29 (20). Calculated:
M 422.31.
1
(C–O–C). H NMR spectrum (500 MHz), δ, ppm:
2.96 t (4H, NCH2), 3.65 t (4H, OCH2), 7.36 d (1H,
3
3
5′-H, J = 3.5 Hz), 7.57 d (1H, 4′-H, J = 3.5 Hz),
3
4
7.86 d.d (1H, 4-H, J = 8.5, J = 1.9 Hz), 7.89 d (1H,
3
4
3-H, J = 8.5 Hz), 7.99 d (1H, 6-H, J = 1.9 Hz),
12.89 s (1H, NH). Mass spectrum, m/z (Irel, %): 352 (8)
[M – Cl]+, 290 (9), 288 (25), 240 (15), 238 (39), 210
(10), 205 (10), 203 (33), 202 (7), 155 (10), 141 (12),
140 (13), 139 (37), 138 (32), 127 (8), 112 (13), 111
(13), 110 (40), 86 (39), 84 (9), 75 (28), 74 (7), 58 (9),
57 (15), 56 (100), 55 (24), 54 (8), 45 (15), 44 (10), 42
(16), 41 (8), 30 (19), 29 (38), 28 (18), 27 (13), 15 (7).
Calculated: M 387.86.
2,4-Dichloro-5-(phenylsulfamoyl)-N-(1,3-thiazol-
2-yl)benzamide (4h) was synthesized from 1 g of
sulfonyl chloride 3c. Yield 0.624 g (54%), light brown
crystals, mp 287–290°C. IR spectrum, ν, cm–1: 3268
(SO2N–H); 3181 (CON–H); 3079 (C–Harom); 1679,
1658 (C=O, C=N); 1582 (C=Carom); 1556 (δN–H,
Compounds 4f, 4g, 4i, 4j, and 4l were synthesized
in a similar way.
1
C=N); 1488 (C=Carom); 1346, 1159 (SO2). H NMR
3
spectrum (400 MHz), δ, ppm: 7.04 t (1H, p-H, J =
2-Chloro-5-(phenylsulfamoyl)-N-(1,3-thiazol-
2-yl)benzamide (4e) was synthesized from 1.5 g of
sulfonyl chloride 3b. Yield 1.347 g (77%), white
crystals, mp 204–206°C. IR spectrum, ν, cm–1: 3257
(SO2N–H), 3182 (CON–H), 1682 (C=O), 1593
(C=Carom), 1572 (δN–H, C=N), 1492 (C=Carom), 1347,
3
7.7 Hz), 7.12 d (2H, o-H, J = 7.7 Hz), 7.25 t (2H,
3
3
m-H, J = 7.7 Hz), 7.35 d (1H, 5′-H, J = 3.4 Hz),
7.56 d (1H, 4′-H, 3J = 3.4 Hz), 8.03 s (1H, 3-H), 8.28 s
(1H, 6-H), 10.82 s (1H, SO2NH), 12.94 s (1H, CONH).
Found, %: C 44.73; H 2.61; N 9.68; S 14.69.
C16H11Cl2N3O3S2. Calculated, %: C 44.87; H 2.59;
N 9.81; S 14.97.
1
1169 (SO2). H NMR spectrum (400 MHz), δ, ppm:
3
3
7.07 t (1H, p-H, J = 7.6 Hz), 7.11 d (2H, o-H, J =
3
2,4-Dichloro-5-(piperidine-1-sulfonyl)-N-(1,3-
thiazol-2-yl)benzamide (4i) was synthesized from 1 g
of sulfonyl chloride 3c. Yield 0.676 g (60%), light
brown plates, mp 193–196°C. IR spectrum, ν, cm–1:
3191 (N–H); 1679 (C=O); 1551 (δN–H, C=N); 1302,
7.6 Hz), 7.26 t (2H, m-H, J = 7.6 Hz), 7.35 d (1H,
3
3
5′-H, J = 3.5 Hz), 7.56 d (1H, 4′-H, J = 3.5 Hz),
3
3
7.77 d (1H, 3-H, J = 8.5 Hz), 7.84 d.d (1H, 4-H, J =
8.5, 4J = 2.1 Hz), 7.99 d (1H, 6-H, 4J = 2.1 Hz), 10.43 s
(1H, SO2NH), 12.87 s (1H, CONH). Found, %:
C 48.90; H 3.09; N 10.77; S 16.50. C16H12ClN3O3S2.
Calculated, %: C 48.79; H 3.07; N 10.67; S 16.28.
1
1166 (SO2). H NMR spectrum (400 MHz), δ, ppm:
1.51 m (6H, CH2), 3.32 t (4H, NCH2), 7.35 d (1H,
3
3
5′-H, J = 3.6 Hz), 7.57 d (1H, 4′-H, J = 3.6 Hz),
8.08 s (1H, 3-H), 8.19 s (1H, 6-H), 12.48 s (1H, NH).
Found, %: C 43.03; H 3.63; N 9.89; S 15.01.
C15H15Cl2N3O3S2. Calculated, %: C 42.86; H 3.60;
N 10.00; S 15.26.
2-Chloro-5-(piperidine-1-sulfonyl)-N-(1,3-thia-
zol-2-yl)benzamide (4f). Yield 1.226 g (71%), white
plates, mp 221–223°C. IR spectrum, ν, cm–1: 3164
(N–H); 1675, 1662 (C=O, C=N), 1587 (C=Carom), 1567
1
(δN–H, C=N), 1340, 1165 (SO2). H NMR spectrum
(400 MHz), δ, ppm: 1.46 m (6H, CH2), 2.94 t (4H,
NCH2), 7.35 d (1H, 5′-H, J = 3.6 Hz), 7.57 d (1H,
2-Bromo-5-(morpholine-4-sulfonyl)-N-(1,3-thia-
zol-2-yl)benzamide (4j) was synthesized from 1 g of
3
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 1 2016

SHLENEV et al.
74
sulfonyl chloride 3d. Yield 0.711 g (63%), white crys-
tals, mp 190–192°C. IR spectrum, ν, cm–1: 3180
(N–H); 1672 (C=O); 1587 (C=Carom, δN–H, C=N);
1356, 1163 (SO2); 1114, 944 (C–O–C). 1H NMR spec-
trum (500 MHz), δ, ppm: 2.96 t (4H, NCH2), 3.65 t
b. A solution of 1 g (2.6 mmol) of compound 4d in
10 mL of diphenyl ether was heated for 2 h under
reflux with vigorous stirring. The mixture was diluted
with 10 mL of decane, and the precipitate was filtered
off, washed with butan-1-ol (3×10 mL), and purified
by double recrystallization from DMF–water (5:2 by
volume). Yield 0.221 g (24%), mp 320–324°C. IR
spectrum, ν, cm–1: 3139 (C–Hthiaz), 3091 (C–Harom),
1605 (C=Cthiaz), 1588 (C=Carom), 1648 (C=O), 1567
(C=N), 1509 (C=Carom), 1352, 1166 (SO2), 1109, 948
3
(4H, OCH23), 7.36 d (1H, 5′-H, J = 3.7 Hz), 7.57 d
3
(1H, 4′-H, J = 3.7 Hz), 7.76 d.d (1H, 4-H, J = 8.5,
4J = 2.2 Hz), 7.93 d (1H, 6-H, 4J = 2.2 Hz), 8.03 d (1H,
3
3-H, J = 8.5 Hz), 12.84 s (1H, NH). Mass spectrum,
m/z (Irel, %): 352 (9) [M – Br]+, 334 (10), 332 (11), 284
(17), 282 (15), 249 (14), 247 (12), 185 (15), 184 (15),
183 (16), 182 (14), 156 (16), 155 (5), 154 (17), 86
(31), 76 (8), 75 (37), 74 (10), 58 (9), 57 (13), 56 (100),
55 (28), 45 (18), 42 (18), 30 (17), 29 (35), 28 (14), 27
(12). Calculated: M 432.31.
1
(C–O–C). H NMR spectrum (500 MHz), δ, ppm:
2.94 t (4H, NCH2), 3.65 t (4H, OCH2), 7.49 d (1H,
3
3
4
2-H, J = 5.0 Hz), 8.17 d.d (1H, 8-H, J = 8.8, J =
4
2.2 Hz), 8.42 d (1H, 6-H, J = 2.2 Hz), 8.46 d (1H,
3
3
9-H, J = 8.8 Hz), 8.60 d (1H, 1-H, J = 5.0 Hz).
13C NMR spectrum (125 MHz), δC, ppm: 45.92
(CH2N), 65.31 (CH2O), 110.61 (C2), 118.13 (C9),
118.19 (C5a), 123.52 (C1), 128.01 (C6), 131.66 (C8),
132.75 (C7), 139.68 (C9a), 164.08 (C5), 167.66 (C3a).
Mass spectrum, m/z (Irel, %): 351 (1) [M]+, 216 (8), 202
(12), 201 (10), 86 (74), 75 (14), 73 (15), 58 (20), 57
(10), 56 (100), 55 (10), 45 (10), 44 (32), 42 (26), 41
(12). Calculated: M 351.40.
2-Bromo-5-(phenylsulfamoyl)-N-(1,3-thiazol-
2-yl)benzamide (4k) was synthesized from 1 g of
sulfonyl chloride 3d. Yield 0.751 g (65%), light brown
crystals, mp 204–206°C. IR spectrum, ν, cm–1: 3196,
3097 (N–H); 1660 (C=O); 1589 (C=Carom); 1567
(δN–H, C=N); 1495 (C=Carom); 1346, 1164 (SO2).
1H NMR spectrum (400 MHz), δ, ppm: 7.07 t (1H,
p-H, 3J = 7.4 Hz), 7.11 d (2H, o-H, 3J = 7.4 Hz), 7.26 t
(2H, m-H, 3J = 7.4 Hz), 7.35 d (1H, 5′-H, 3J = 3.6 Hz),
7.55 d (1H, 4′-H, 3J = 3.6 Hz), 7.73 d.d (1H, 4-H, 3J =
8.4, 4J = 2.2 Hz), 7.94–7.92 m (2H, 3-H, 6-H), 10.42 s
(1H, SO2NH), 12.86 s (1H, CONH). Found, %:
C 43.70; H 2.72; N 9.51; S 14.86. C16H11Cl2N3O3S2.
Calculated, %: C 43.84; H 2.76; N 9.59; S 14.63.
Compounds 5b and 5c were synthesized in a simi-
lar way according to methods a and b from 4b or 4e
and 4c or 4f, respectively.
7-(Phenylsulfamoyl)-5H-[1,3]thiazolo[3,2-a]quin-
azolin-5-one (5b). Yield 0.208 g (55%), light brown
crystals, mp 317–319°C (a); 0.240 g (26%), mp 312–
316°C (b). IR spectrum, ν, cm–1: 3285 (N–H), 3123
(C–Hthiaz), 1648 (C=O), 1608 (C=Cthiaz), 1590
(C=Carom), 1567 (C=N), 1506 (C=Carom), 1338, 1159
2-Bromo-5-(piperidine-1-sulfonyl)-N-(1,3-thia-
zol-2-yl)benzamide (4l) was synthesized from 1 g of
sulfonyl chloride 3d. Yield 0.589 g (52%), light brown
plates, mp 197–200°C. IR spectrum, ν, cm–1: 3161,
3132 (N–H); 1680 (C=O); 1563 (δN–H, C=N); 1342,
1
(SO2). H NMR spectrum (400 MHz), δ, ppm: 7.03 t
3
3
(1H, p-H, J = 7.8 Hz), 7.10 d (2H, o-H, J = 7.8 Hz),
1
3
3
1167 (SO2). H NMR spectrum (400 MHz), δ, ppm:
7.23 t (2H, m-H, J = 7.8 Hz), 7.43 d (1H, 2-H, J =
4.8 Hz), 8.09 d.d (1H, 8-H, J = 8.9, J = 2.0 Hz),
8.32 d (1H, 9-H, J = 8.9 Hz), 8.45 d (1H, 1-H, J =
4.8 Hz), 8.52 d (1H, 6-H, J = 2.0 Hz), 10.45 s (1H,
3
4
1.60–1.34 m (6H, CH2), 2.94 t (4H, NCH2), 7.35 d
(1H, 5′-H, 3J = 3.5 Hz), 7.56 d (1H, 4′-H, 3J = 3.5 Hz),
3
3
3
4
4
7.75 d.d (1H, 4-H, J = 8.3, J = 2.2 Hz), 7.91 d (1H,
4
3
6-H, J = 2.2 Hz), 8.00 d (1H, 3-H, J = 8.3 Hz),
12.85 s (1H, NH). Found, %: C 41.98; H 3.72; N 9.90;
S 15.12. C15H16BrN3O3S2. Calculated, %: C 41.86;
H 3.75; N 9.76; S 14.90.
NH). Found, %: C 53.60; H 3.13; N 11.88; S 18.23.
C16H11N3O3S2. Calculated, %: C 53.77; H 3.10;
N 11.76; S 17.94.
7-(Piperidine-1-sulfonyl)-5H-[1,3]thiazolo[3,2-a]-
quinazolin-5-one (5c). Yield 0.216 g (59%), light
brown crystals, mp 264–266°C (a); 0.213 g (23%),
mp 261–265°C (b). IR spectrum, ν, cm–1: 3136
(C–Hthiaz), 1641 (C=O), 1604 (C=Cthiaz), 1583
(C=Carom), 1564 (C=N), 1504 (C=Carom), 1342, 1166
7-(Morpholine-4-sulfonyl)-5H-[1,3]thiazolo-
[3,2-a]quinazolin-5-one (5a). a. A solution of 0.4 g
(1.1 mmol) of compound 4a in 2 mL of DMF was
heated for 3 h under reflux. The mixture was poured
into 3 mL of distilled water, and the precipitate was
filtered off and recrystallized from DMF–acetonitrile–
water (2:1:1 by volume). Yield 0.222 g (59%), light
brown crystals, mp 324–326°C.
1
(SO2). H NMR spectrum (400 MHz), δ, ppm: 1.54 m
3
(6H, CH2), 2.94 t (4H, NCH2), 7.48 d (1H, 2-H, J =
3
4
4.9 Hz), 8.16 d.d (1H, 8-H, J = 8.7, J = 2.2 Hz),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 1 2016

SYNTHESIS OF NEW SULFONAMIDE DERIVATIVES
75
4
3
3
3
8.39 d (1H, 6-H, J = 2.2 Hz), 8.43 d (1H, 9-H, J =
(1H, 2-H, J = 4.9 Hz), 7.65 t (2H, m-H, J = 7.9 Hz),
3
3
3
8.7 Hz), 8.59 d (1H, 1-H, J = 4.9 Hz). Found, %:
C 51.66; H 4.30; N 12.19; S 18.58. C15H15N3O3S2. Cal-
culated, %: C 51.56; H 4.33; N 12.03; S 18.35.
7.72 t (1H, p-H, J = 7.9 Hz), 8.05 d (2H, o-H, J =
3
7.9 Hz), 8.39 d (1H, 8-H, J = 8.9 Hz), 8.42 d (1H,
9-H, 3J = 8.9 Hz), 8.53 d (1H, 1-H, 3J = 4.9 Hz), 8.61 s
(1H, 6-H). Mass spectrum, m/z (Irel, %): 342 (6) [M]+,
173 (16), 161 (14), 77 (100), 75 (28), 63 (13), 58 (16),
51 (54), 50 (12), 44 (29). Calculated: M 342.39.
Compounds 5d–5f and 7 were synthesized as de-
scribed above for 5a (method a) from 4g–4i and 6,
respectively.
8-Chloro-7-(morpholine-4-sulfonyl)-5H-[1,3]-
thiazolo[3,2-a]quinazolin-5-one (5d). Yield 0.184 g
(50%), light brown crystals, mp 335–337°C. IR spec-
trum, ν, cm–1: 3138 (C–Hthiaz); 1635 (C=O, C=N);
1600, 1582 (C=Carom); 1563 (C=N); 1333, 1165 (SO2);
REFERENCES
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and El-Subbagh, H.I., Eur. J. Med. Chem., 2012,
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1
1111, 941 (C–O–C). H NMR spectrum (500 MHz), δ,
2. Hassan, G.S., Med. Chem. Res., 2014, vol. 23, no. 1,
ppm: 3.21 t (4H, NCH2), 3.62 t (4H, OCH2), 7.48 d
p. 388.
3
3
(1H, 2-H, J = 5.0 Hz), 8.57 d (1H, 1-H, J = 5.0 Hz),
8.63 s (1H, 9-H), 8.69 s (1H, 6-H). Mass spectrum, m/z
(Irel, %): 350 (3) [M – Cl]+, 86 (37), 58 (14), 57 (9), 56
(100), 55 (11), 44 (23), 42 (17), 41 (9), 30 (16), 29
(37), 28 (19), 27 (13). Calculated: M 385.85.
3. El-Gazzar, A.B.A., Youssef, M.M., Youssef, A.M.S.,
Abu-Hashem, A.A., and Badria, F.A., Eur. J. Med.
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6. Nosova, E.V., Lipunova, G.N., Kravchenko, M.A.,
Laeva, A.A., and Charushin, V.N., Pharm. Chem. J.,
2008, vol. 42, no. 4, p. 169.
8-Chloro-7-(phenylsulfamoyl)-5H-[1,3]thiazolo-
[3,2-a]quinazolin-5-one (5e). Yield 0.197 g (54%),
light brown crystals, mp 276–278°C. IR spectrum, ν,
cm–1: 3267 (N–H); 3078 (C–Harom); 1637 (C=O, C=N);
1599, 1582 (C=Carom); 1569 (C=N); 1485 (C=Carom);
1
1341, 1167 (SO2). H NMR spectrum (400 MHz), δ,
3
ppm: 7.23 t (2H, p-H, J = 7.8 Hz), 7.12 d (2H, o-H,
7. Pellon, R.F. and Docampo, M.L., Synth. Commun.,
3
3J = 7.8 Hz), 7.23 t (2H, m-H, J = 7.8 Hz), 7.43 d
2007, vol. 37, p. 1853.
3
3
(1H, 2-H, J = 4.9 Hz), 8.49 d (1H, 1-H, J = 4.9 Hz),
8.59 s (1H, 9-H), 8.68 s (1H, 6-H), 10.81 s (1H, NH).
Found, %: C 48.93; H 2.53; N 10.59; S 16.67.
C16H10ClN3O3S2. Calculated, %: C 49.04; H 2.57;
N 10.72; S 16.37.
8. Bakherad, M., Keivanloo, A., Kalantar, Z., and
Keley, V., Phosphorus, Sulfur Silicon Relat. Elem.,
2011, vol. 186, p. 464.
9. Yadav, A.K., Dhakad, P., and Sharma, G.R., Tetrahedron
Lett., 2013, vol. 54, p. 6061.
10. Behbehani, H. and Ibrahim, H.M., Chem. Cent. J., 2013,
8-Chloro-7-(piperidine-1-sulfonyl)-5H-[1,3]thia-
zolo[3,2-a]quinazolin-5-one (5f). Yield 0.185 g
(51%), white crystals, mp 326–329°C. IR spectrum, ν,
cm–1: 3139 (C–Hthiaz); 3095 (C–Harom); 1628 (C=O,
C=N); 1597, 1582 (C=Carom); 1566 (C=N); 1488
vol. 7, p. 82.
11. Zborovskii, Yu.L., Orysyk, V.V., Dobosh, A.A., Stani-
nets, V.I., Pirozhenko, V.V., and Chernega, A.N., Chem.
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Lipunova, G.N., and Charushin, V.N., Heteroatom
Chem., 2006, vol. 17, no. 6, p. 579.
1
(C=Carom); 1340, 1170 (SO2). H NMR spectrum
(400 MHz), δ, ppm: 1.52 m (6H, CH2), 3.20 t (4H,
NCH2), 7.47 d (1H, 2-H, 3J = 4.9 Hz), 8.56 d (1H, 1-H,
3J = 4.9 Hz), 8.62 s (1H, 6-H), 8.66 s (1H, 9-H).
Found, %: C 46.79; H 3.70; N 11.04; S 16.46.
C15H14ClN3O3S2. Calculated, %: C 46.93; H 3.68;
N 10.95; S 16.71.
13. Nosova, E.V., Lipunova, G.N., and Charushin, V.N.,
Russ. Chem. Rev., 2009, vol. 78, no. 5, p. 387.
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shin, V.N., Russ. J. Org. Chem., 2005, vol. 41, no. 11,
p. 1671.
7-(Benzenesulfonyl)-5H-[1,3]thiazolo[3,2-a]quin-
azolin-5-one (7). Yield 0.169 g (47%), white crystals,
mp 343–346°C. IR spectrum, ν, cm–1: 3139 (C–Hthiaz);
3072 (C–Harom); 1628 (C=O, C=N); 1601, 1588
(C=Carom); 1567 (C=N); 1500 (C=Carom); 1306, 1153
15. Tarasov, A.V., Strikanova, O.N., Moskvichev, Yu.A.,
and Timoshenko, G.N., Russ. J. Org. Chem., 2002,
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16. Moskvichev, Yu.A., Tarasov, A.V., Alov, E.M., and
Gerasimova, N.P., Ross. Khim. Zh., 2005, vol. 49,
no. 6, p. 21.
1
(SO2). H NMR spectrum (500 MHz), δ, ppm: 7.45 d
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 1 2016