Quinazolines 1. Synthesis and chemical reactions of 6-chlorosulfonyl- quinazoline-2,4-diones

Article abstract of DOI:10.1007/s10593-008-0048-y

Treatment of quinazoline-2,4-dione and its symmetrical 1,3-dialkyl derivatives with chlorosulfonic acid gave the corresponding 6- chlorosulfonylquinazoline-2,4-diones. Reaction of the compounds obtained with nucleophilic agents (water, ammonia, aliphatic and cyclic amines) gave the corresponding free 2,4-dioxoquinazoline-6-sulfonic acids, 6- sulfamidoquinazoline-2,4-diones, and 2,4-dioxoquinazoline-6-sulfonic acid amides.

Full text of DOI:10.1007/s10593-008-0048-y

Chemistry of Heterocyclic Compounds, Vol. 44, No. 3, 2008
QUINAZOLINES
1. SYNTHESIS AND CHEMICAL
REACTIONS OF 6-CHLOROSULFONYL-
QUINAZOLINE-2,4-DIONES
R. Sh. Kuryazov, N. S. Mukhamedov, and Kh. M. Shakhidoyatov
Treatment of quinazoline-2,4-dione and its symmetrical 1,3-dialkyl derivatives with chlorosulfonic acid
gave the corresponding 6-chlorosulfonylquinazoline-2,4-diones. Reaction of the compounds obtained
with nucleophilic agents (water, ammonia, aliphatic and cyclic amines) gave the corresponding free 2,4-
dioxoquinazoline-6-sulfonic acids, 6-sulfamidoquinazoline-2,4-diones, and 2,4-dioxoquinazoline-
6-sulfonic acid amides.
Keywords: 2,4-dioxoquinazoline-6-sulfonic acid amides, 2,4-dioxoquinazoline-6-sulfonic acids,
symmetrical 1,3-dialkylquinazoline-2,4-diones, 6-chlorosulfonylquinazoline-2,4-diones, nucleophilic
and electrophilic substitution.
Within the series of quinazoline derivatives there are found fungicides, bactericides, insecticides, and
plant growth regulators [1]. Amongst them there are also found substances having anticholinesterase, soporific,
antispasmodic, sedative, tranquilizing, muscle relaxing, antirheumatic, hypotensive, bronchodilating, diuretic,
antimalarial, and other activities [1-8].
We have previously studied the chlorosulfonylation of benzoxazolin-2-ones [9] and benzothiazolin-
2-ones [10] and synthesized the corresponding 6-chlorosulfonylbenzazolin-2-ones. In continuing investigation of
electrophilic substitution in a series of nitrogen-containing heterocyclic compounds [9-13] it was of interest to
study the chlorosulfonylation of quinazoline-2,4-dione and its symmetrical 1,3-dialkyl derivatives and to carry
out chemical reactions of the compounds obtained.
It was found that the reaction of the quinazoline-2,4-diones 1a-d with chlorosulfonic acid (CSA) forms
the corresponding 6-chlorosulfonylquinazoline-2,4-diones 2a-d regardless of the reagent ratio. The best yields
are obtained with a molar ratio of the reagents 1a-d to CSA of 1:5. This is likely due to the ease of the
nucleophilic substitution reaction of the hydroxyl group of the intermediate sulfonic acids 3a-d for the chlorine
atom of the CSA due to the increased positive charge of the sulfur atom of the sulfo group.
The free 2,4-dioxoquinazoline-6-sulfonic acids 3a-d could be synthesized in quantitative yields
(Table 1) by hydrolysis of the corresponding 6-chlorosulfonylquinazoline-2,4-diones 2a-d. It should be noted
that the rate of the hydrolysis decreases with lengthening of the alkyl chain in the 1,3-dialkyl-6-chlorosulfonyl-
quinazoline-2,4-diones 2c,d. Thus if the conversion of the sulfochlorides 2a,b to the corresponding sulfonic
acids 3a,b needs heating for 2 h the hydrolysis of compounds 2c,d requires 6 and 10 h respectively.
__________________________________________________________________________________________
S. Yu. Yunusov Institute of the Chemistry of Plant Substances, Academy of Sciences Republic of
Uzbekistan, Tashkent 700170; e-mail: nasirxon@rambler.ru. Translated from Khimiya Geterotsiklicheskikh
Soedinenii, No. 3, pp. 420-427, March 2008. Original article submitted December 11, 2007; revision submitted
January 25, 2008.
324
0009-3122/08/4403-0324©2008 Springer Science+Business Media, Inc.

O
HO
O
O
R
O
S
R
O
N
ClSO3H
O
N
N
R
N
R
3a–d
1a–d
H2O
R
ClSO3H
ClSO3H
Cl
O
O
O
S
X
HN
N
H2N
O
NH3
O
N
R
O
X
S
R
O
O
N
2a–d
N
O
O
N
R
R1
S
R
O
O
N
HN
O
4a–d
R1
R1
N
N
R
R1
O
S
6a–h
R
O
O
N
N
R
5a–h
1–4 a R = H, b R = Me, c R = n-Pr; d R = n-Bu; 5, 6 a, e R = H, b, f R = Me, c, g R = n-Pr,
d, h R = n-Bu; 5 a–d R1 = Et, e–h R1 = n-Bu; 6 a–d X = CH2, e–h X = O
It should also be noted that the sulfonic acids 3a-d react smoothly with CSA in quantitative yields to
give the corresponding 6-chlorosulfonylquinazoline-2,4-diones 2a-d.
The reactions of compounds 2a-d with ammonia and with aliphatic and heterocyclic amines takes place
smoothly independently of the length of the alkyl groups in positions 1 and 3. Refluxing compounds 2a-d with
concentrated ammonia solution gave the corresponding 6-sulfamidoquinazoline-2,4-diones 4a-d. Reaction of
compounds 2a-d with aliphatic amines in the presence of triethylamine at room temperature gives high yields of
the corresponding N,N-dialkylamides of 2,4-dioxoquinazoline-6-sulfonic acids 5a-h and with heterocyclic
amines the 2,4-dioxoquinazoline-6-sulfonic acid morpholide and piperidide (Table 1). It is likely that the
basicity of the amine used is a determining factor in these reactions.
1
The structure of the synthesized compounds 2-6 was identified by IR and H NMR spectroscopy, mass
spectrometry, and was confirmed by elemental analytical data.
The IR spectra of compounds 2-6 show characteristic absorption bands for the asymmetric and
symmetric stretching vibrations of the SO2 groups in the region 1100-1400 cm-1. The free 2,4-dioxoquinazoline-
6-sulfonic acids 3a-d in addition show stretching absorptions for the S–O group at 600-700 cm-1 (Table 2).
The mass spectra of compounds 2-6 show molcular ions and fragments fully confirming the proposed
structures. The mass spectra of compounds 4-6 show a common fragmentation with fission of the SO2–NR1
2
bond to give the fragments A [M+–NR1 ] and B [NR1 ] independently of the nature of the R and R1 substituent.
2
2
It was found that the M+ molcular ion peaks in compounds 4a-d have maximum intensity whereas in
compounds 5a-h, 6a-h the fragment A peaks are a maximum. Hence the first fragmentation act in compound 2a
is fission of the S–Cl bond whereas in the sulfochlorides 2b-d the 1,3-dialkyl substituents separate. The
fragmentation route associated with elimination of the quinazoline-2,4-dione ring is expressed weakly.
325

TABLE 1. Physicochemical Characteristics for the Compounds Prepared 2-6
mp., °C
(Solvent
for recrystallization)
Found N, %
Com-
pound
Empirical
formula
Yield, %
(method)
——————
Calculated N, %
C8H5ClN2O4S
77 (A)
95 (B)
2a
11.02
10.74
307-309 (Heptane)
C10H9ClN2O4S
C14H17ClN2O4S
C16H21ClN2O4S
C8H6N2O5S
9.51
9.70
7.83
8.12
7.80
7.51
11.21
11.57
10.01
10.37
8.89
8.58
8.21
7.90
17.08
17.42
15.87
15.61
13.04
12.32
11.67
11.89
13.86
14.14
12.61
12.92
10.86
11.02
10.61
10.26
12.21
11.89
10.77
11.02
10.02
9.61
8.74
9.03
13.21
13.59
12.09
12.46
10.89
10.68
10.28
9.97
13.82
13.50
2b
2c
2d
3a
3b
3c
3d
4a
4b
4c
4d
5a
5b
5c
5d
5e
5f
146-14 (Hexane)
74
72
67
95
91
96
91
86
96
97
95
80
87
92
89
80
97
95
79
85
89
92
89
87
90
96
96-97 (Benzene)
84-85 (Chloroform)
365-367 (Water)
C10H10N2O5S
C14H18N2O5S
C16H22N2O5S
C8H7N3O4S
236-238 (Water)
182-184 (Water)
72–73 (Water)
334-336 (Ethanol)
C10H11N3O4S
C14H19N3O4S
C16H23N3O4S
C12H15N3O4S
C14H19N3O4S
C18H27N3O4S
C20H31N3O4S
C16H23N3O4S
C18H27N3O4S
C22H35N3O4S
C24H39N3O4S
C13H15N3O4S
C15H19N3O4S
C19H27N3O4S
C21H31N3O4S
C12H13N3O5S
C14H17N3O5S
C18H25N3O5S
270-271 (Aqueous ethanol)
230-232 (Aqueous ethanol)
206-208 (Aqueous ethanol)
300-302 (Methanol)
214-216 (Methanol)
146-148 (Aqueous methanol)
112-113 (Aqueous methanol)
225-227 (Ethanol)
138-140 (Aqueous ethanol)
86-88 (Aqueous ethanol)
82-83 (Aqueous ethanol)
304-306 (Ethanol)
5g
5h
6a
6b
6c
6d
6e
6f
246-248 (Aqueous ethanol)
164-166 (Aqueous ethanol)
138-140 (Benzene)
302-303 (Ethanol)
12.09
12.38
10.21
10.63
244-246 (Aqueous ethanol)
142-144 (Aqueous ethanol)
6g
The 1H NMR spectra of compounds 2-6 (Table 2) also confirm the proposed structures. The quinazoline-
2,4-dione ring region of the spectrum shows a doublet for proton H-5 at 8.25-8.47 ppm (mJ = 2.3 Hz), a double
doublet for protons H-7 at 7.80-7.93 ppm (oJ = 8.8-9.2 and mJ = ~2.3 Hz), and a double
326

327

for proton H-8 at 7.20-7.30 ppm (oJ = 8.8-9.2 Hz). The NH group protons are seen at low field
(9.20-10.10 ppm). The protons of the 1,3-dialkyl and alkyl residues in the amide groups are seen at high field
(0.46-3.57 ppm) (Table 2).
EXPERIMENTAL
The IR spectra of the compounds studied were obtained on a UR-20 spectrometer using vaseline oil. 1H
NMR spectra were taken on a UNITY 400+ instrument (400 MHz) using CD3COOD and with TMS as internal
standard. Mass spectra were registered on a Kratos MS-30 instrument with direct introduction of the sample into
the ion source (ionization energy 70 eV). Monitoring of the reaction course and purity of the compounds
prepared was carried out by TLC on Silufol UV-254 plates in a solvent system of benzene–acetone (10:1) and
revealed using a solution of KMnO4 (1 g), H2SO4 (4 ml), and water (96 ml).
The quinazoline-2,4-dione (1a) was prepared by cyclization of anthranilic acid with urea [14] and the
symmetrical 1,3-dialkylquinazoline-2,4-diones 1b-d by alkylation of compound 1a with the corresponding alkyl
halides under phase-transfer catalytic reaction conditions [15].
6-Chlorosulfonylquinazoline-2,4-dione (2a). A. Compound 1a (1.62 g, 10 mmol) was added
portionwise with stirring to chlorosulfonic acid (5.83 g, 50 mmol) cooled to 5-10ºC at such a rate that the
reaction temperature did not exceed 15ºC.
The reaction mixture was heated to 50-60ºC, held at this temperature for 6 h, and poured into crushed
ice. The precipitate formed was filtered off, washed with water, and recrystallized from heptane. Yield 2.0 g.
B. 2,4-Dioxoquinazoline-6-sulfonic acid (3a) (2.42 g, 10 mmol) was added portionwise to
chlorosulfonic acid (2.33 g, 20 mmol) cooled to 0ºC at such a rate that the temperature did not exceed 10ºC. The
mixture was heated to 50-60ºC, held at this temperature for 2 h, and poured onto crushed ice. The precipitate
obtained was filtered off, washed with water, and recrystallized from heptane. Yield 2.47 g.
6-Chlorosulfonylquinazoline-2,4-diones 2b-d were prepared similarly.
2,4-Dioxoquinazoline-6-sulfonic Acid (3a). A mixture of compound 2a (2.6 g, 10 mmol) in water
(20 ml) was refluxed for 2 h and the solvent was partially distilled off. The precipitate obtained was filtered off
and recrystallized from water. Yield 2.29 g.
2,4-Dioxoquinazoline-6-sulfonic Acids 3b-d were synthesized similarly.
6-Sulfonamidoquinazoline-2,4-dione (4a). A mixture of compound 2a (2.6 g, 10 mmol) in
concentrated ammonia (100 ml) was heated for 2 h with stirring and left overnight. The precipitate obtained was
filtered off and recrystallized from ethanol. Yield 2.07 g.
6-Sulfonamidoquinazoline-2,4-diones 4b-d were prepared similarly (Table 1).
2,4-Dioxoquinazoline-6-sulfonic Acid N,N-diethylamide (5a). A mixture of diethylamine (0.73 g,
10 mmol) and triethylamine (1.01 g, 10 mmol) in acetone (15 ml) was added dropwise to a solution of
compound 2a (2.6 g, 10 mmol) in acetone (30 ml). The product was stirred at room temperature for 2 h, acetone
evaporated off, and water (100 ml) was added to the residue. The precipitate obtained was filtered off and
recrystallized from methanol. Yield 2.37 g.
2,4-Dioxoquinazoline-6-sulfonic Acid N,N-diethyl- and N,N-di-n-butylamides 5b-h were prepared
similarly.
2,4-Dioxoquinazoline-2,4-sulfonic Acid N-piperidide (6a) was prepared similarly to compound 5a
from compound 2a (2.6 g, 10 mmol), piperidine (0.85 g, 10 mmol), and triethylamine (1.01 g, 10 mmol). Yield
2.62 g.
2,4-Dioxoquinazoline-6-sulfonic Acid N-piperidide and N-morpholide 6b-h were synthesized
similarly.
328

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