Synthesis of thiazino- and thiazoloquinazolinones by cyclization of S-(2-propenyl) derivatives of 2-thioxo-2,3-dihydro-4(1H)-quinazolinone

Article abstract of DOI:10.1023/A:1025154317771

Interaction of potassium salts of quinazolin-2-thiol-4-one with γ-substituted allyl halides gave thiazoloquinazolinones with linear or angular structures depending on the structure of the carbonyl radical. S-Allyl substituted quinazolin-2-thiol-4-one reac

Full text of DOI:10.1023/A:1025154317771

Chemistry of Heterocyclic Compounds, Vol. 39, No. 5, 2003
SYNTHESIS OF THIAZINO- AND THIAZOLO-
QUINAZOLINONES BY CYCLIZATION OF
S-(2-PROPENYL) DERIVATIVES OF 2-THIOXO-
2,3-DIHYDRO-4(1H)-QUINAZOLINONE
V. V. Orysyk1, Yu. L. Zborovskii2, V. I. Staninets2, A. A. Dobosh1, and S. M. Khripak1
Interaction of potassium salts of quinazolin-2-thiol-4-one with γ-substituted allyl halides gave
thiazoloquinazolinones with linear or angular structures depending on the structure of the carbonyl
radical. S-Allyl substituted quinazolin-2-thiol-4-one reacted with halogens to give iminium salts of
thiazinoquinazolinone with an angular structure. The conversion of these salts to the corresponding
bases and thiazoloquinazolinones has been studied.
Keywords: thiazinoquinazolinones, thiazoloquinazolinones, cyclization, rearrangement.
Condensed derivatives of pyrimidine play a major role in metabolic processes and their synthetic
analogs possess a wide spectrum of physiological activities [1, 2] and consequently they have been much
studied.
However, tricyclic systems in which the pyrimidine ring is condensed with a benzene and a thiazole (or
thiazine) ring have not been adequately studied. A method for the synthesis of linear tricyclic systems
containing benzene, pyrimidine, and thiazole rings by the cyclization of 2-mercapto-3-(2-propenyl)-4(1H)-
quinazolinones reacting with bromine has been described [3].
Cyclization of derivatives of S-allylquinazolin-2-thion-4-one to produce tricyclic compounds containing
the thiazino(thiazolo)quinazolinones fragments with linear and angular structures is described in this paper.
It is known that alkylation of salts of quinazolin-2-thiol-4-ones with alkyl halides occurs with the
formation of 2-S-alkyl derivatives [4]. We have established that alkylation of the potassium salt of quinazolin-2-
thiol-4-one (1) with cinnamyl chloride gave analogously the S-alkenyl derivative 2. However, when an attempt
was made to alkylate salt 1 with ethyl 4-bromocrotonate (3), instead of the expected 2-(3-carboethoxy-2-
propenylthio)-4(3H)quinazolinone (4) we obtained the products of its cyclization, compounds 5 and 6
(Scheme 1).
The formation of these products is explained as follows. The presence of the electron accepting
carboethoxy group on the double bond increases the electrophilicity of the β-carbon atom of the butenyl unit to
a considerable extent which, in its turn, facilitates nucleophilic attack of the equally distant nitrogen atoms N(1)
and N(3) at the stage of intramolecular cyclization of the intermediate 4.
It should be noted that when the reaction was carried out in boiling ethanol only the angular compound
6 was formed, while when the reaction was carried out at a lower temperature (10-15 °C) a mixture of the linear
and angular cyclization products was obtained.
__________________________________________________________________________________________
1 Uzhgorod State University, Uzhgorod 88000, Ukraine. 2 Institute of Organic Chemistry, National Academy
of Sciences of Ukraine, Kiev 02094, Ukraine; e-mail: iochkiev@ukrpack.net. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 5, 739-741, May 2003. Original article submitted October 17, 2000.
640
0009-3122/03/3905-0640$25.00©2003 Plenum Publishing Corporation

Scheme 1
O
O
BrCH2CH=CHCOOEt
NH
PhCH=CHCH2Cl
NH
3
NH
SCH2CH=CHCOOEt
N
SK
1
N
4
O
O
CH2COOEt
O
N
SCH2CH=CHPh
N
2
N
S
N
5
N
S
EtOOCCH2
6
Thiazinoquinazolinones of angular structure, 7a,b, were formed in almost quantitative yield from the
action of bromine or iodine on a solution of compound 2 in acetic acid at 15-20°C. When the reaction was
carried out at a higher temperature or in chloroform slight resin formation occurred with the formation of a
mixture of derivatives of thiazino- and thiazoloquinazolinone.
The yield of compounds 7a,b depends on the amount of halogen used. For example, with a 1:1 molar
ratio of halogen to compound 2 the yield of products 7a,b was 30%. When the ratio was increased to 2:1 for
bromine or 3:1 for iodine compounds 7a,b may be obtained in almost quantitative yield. The bromine derivative
7a is orange yellow, while the iodine derivative 7b is dark brown.
Treatment of the salts 7a,b with sodium acetate gave the corresponding bases 8a,b which lost a
hydrogen halide on treatment with organic bases (morpholine or piperidine) to give compound 9. The
thiazinoquinazolinones 8a,b underwent rearrangement when heated in an ethanol–DMSO mixture to give the
thiazoloquinazolinones 10a,b. The latter, when treated with sodium ethoxide, lost a molecule of hydrogen
halide to give the intermediate 11, which underwent intramolecular rearrangement, accompanied by migration
of the exocyclic double bond into the thiazole ring, to give compound 12 as the final product.
O
O
O
N
9
NH
N
X
N
_
X2
MeCOONa
DMSO
B
2
+
Xn
N
N
S
S
S
Ph
Ph
8a,b
Ph
X
7a,b
∆, DMSO,
EtOH
O
O
N
O
N
N
EtONa
N
N
S
N
S
S
Ph
Ph
Ph
Me
CH2X
CH2
12
11
10a,b
7, 8, 10 a X = Br, n = 3; b X = I, n = 5; B = morpholine, piperidine
641

The composition and structures of the products synthesized were confirmed by elemental analysis and
IR and 1H NMR spectroscopy (Tables 1 and 2). It should be noted that the positions of the absorption bands of
the carbonyl groups in the quinazolone unit in the IR spectra of the thiazino- and thiazoloquinazolinones with
linear and angular structures differ considerably. For example, in the spectra of compounds with an angular
structure this band appears in the 1665-1650 cm-1 range, whereas in the spectra of the linear heterocyclic
systems it appears at 1695-1670 cm-1 [5,6]. We used this observation to confirm the structures of the compounds
synthesized.
TABLE 1. Characteristics of the Compounds Synthesized
Found, %
——————
Com-
pound
Empirical
formula
Yield,
%
Calculated, %
mp, °С
C
H
Hal
—
N
S
C17H14N2OS
C14H14N2O3S
C14H14N2O3S
C17H14Br4N2OS
C17H14I6N2OS
C17H13BrN2OS
C17H13IN2OS
C17H12N2OS
C17H13BrN2OS
C17H13IN2OS
C17H12N2OS
69.61
69.36
4.77
4.79
9.75
9.52
10.36
10.89
191-193
108-109
158-159
202-205
136-137
194-195
187-188
198-200
182-183
196-197
292-293
90
42
84
95
97
88
75
95
82
74
67
2
58.08
4.87
—
9.73
11.03
5
57.92
4.86
9.65
11.04
57.89
57.92
5.00
4.86
—
9.70
9.65
11.00
11.04
6
33.09
2.10
52.71
52.06
4.42
5.12
7а
7b
8а
8b
9
33.26
2.30
4.56
5.22
19.08
19.34
1.15
1.34
70.90
2.46
2.65
2.89
3.04
72.12
54.59
3.40
21.38
21.41
7.42
8.49
54.70
3.51
7.50
8.59
48.50
48.58
3.04
3.12
30.19
6.40
6.67
7.51
7.63
30.20
69.82
4.02
—
9.51
10.89
69.84
4.14
9.58
10.96
54.64
54.70
3.47
3.51
21.42
21.41
7.43
7.50
8.51
8.59
10а
10b
12
48.55
3.07
30.23
6.51
7.54
48.58
3.12
30.20
6.67
7.63
69.84
69.84
4.09
4.14
—
9.54
9.58
10.91
10.96
TABLE 2. Spectroscopic Characteristics of the Compounds Synthesized
IR spectrum,
Com-
pound
1Н NMR spectrum, δ, ppm (J, Hz)
ν(C=O), cm-1
1
2
3
4.10 (2H, d, J = 7.2, CH2); 6.42 (1H, dt, J = 7.2 and J = 15.9,
CH=CH–C6H5); 6.76 (1H, d, J = 15.9, CH=CH–C6H5);
7.23-7.34 (3H, m, ArH); 7.41-7.44 (3H, m, ArH);
7.60-7.63 (1H, m, ArH); 7.76-7.81 (1H, m, ArH);
8.03-8.06 (1H, m, ArH); 12.59 (1H, s, NH)
1.15 (3H, t, J = 7.2, CH3); 2.82 (dd) and 2.95 (dd) (2H, J = 15.8 and
J = 3.6, J = 15.8 and J = 8.7, SCH2); 3.32 (m) and 3.90 (m) (2H,
CH2COO); 4.08 (2H, q, J = 7.2, COOCH2CH3); 5.31 (1H, m, CH);
7.42-7.52 (2H, m, ArH); 7.77 (1H, m, ArH); 8.06 (1H, m, ArH)
1685*
2
1690*
5
1730*2
1.16 (3H, t, J = 7.0, CH3); 2.70 (dd) and 2.95 (dd) (2H, J = 16.0 and
J = 3.2, J = 16.0 and J = 9.2, SCH2); 3.46 (m) and 3.96 (m) (2H,
CH2COO); 4.07 (2H, q, J = 7.0, COOCH2CH3); 5.58 (1H, m, CH);
7.43-7.54 (2H, m, ArH); 7.80 (1H, m, ArH); 8.04 (1H, m, ArH)
1655*
6
1735*2
3.30 (2H, m, CH2); 5.63 (1H, m, SCH2CH); 6.54 (1H, m, CH);
1720*
7а
7.47 (7H, m, ArH); 7.74 (1H, m, ArH); 8.14 (1H, m, ArH)
642

TABLE 2 (continued)
1
2
3
3.10 (2H, m, CH2); 5.58 (1H, m, SCH2CH); 6.46 (1H, m, CH);
7.44 (7H, m, ArH); 7.74 (1H, m, ArH); 8.16 (1H, m, ArH)
1710*
7b
8а
8b
9
3.26 (2H, m, CH2); 5.59 (1H, m, SCH2CH); 6.44 (1H, m, CH):
1660*
1650*
1655*
7.44 (7H, m, ArH); 7.67 (1H, m, ArH); 8.09 (1H, m, ArH)
3.04 (2H, m, CH2); 5.56 (1H, m, SCH2CH); 6.38 (1H, m, CH);
7.46 (7H, m, ArH); 7.68 (1H, m, ArH); 8.09 (1H, m, ArH)
6.49 (1H, dd, J = 6.6 and J = 9.7, SCH=CH); 6,71 (1H, d, J = 9.7,
SCH=CH); 6.90 (1H, d, J = 6.6, CH); 7.28-7.35 (5H, m, ArH);
7.50 (1H, m, ArH); 7.72-7.81 (2H, m, ArH); 8.09 (1H, m, ArH)
4.07 (3H, m, CH2–CH); 6.24 (1H, m, CH); 7.22-7.45 (7H, m, ArH);
1650*
1650*
1650*
10а
10b
12
7.61-7.69 (1H, m, ArH); 8.07 (1H, m, ArH)
3.93 (3H, m, CH2–CH); 6.13 (1H, m, CH); 7.23-7.44 (7H, m, ArH);
7.65 (1H, m, ArH); 8.07 (1H, m, ArH)
2.14 (3H, s, CH3); 6.62 (1H, m, ArH); 7.35 (1H, m, ArH);
7.45 (1H, m, ArH); 7.56-7.64 (5H, m, ArH); 8.17 (1H, m, ArH)
_______
* (C=O of the quinazoline unit).
*2 (C=O of the carbethoxy unit).
EXPERIMENTAL
1
IR spectra of KBr tablets were recorded with a UR-10 instrument. H NMR spectra of DMSO-d6
solutions with TMS as internal standard were recorded on a Varian VXR (300 MHz) machine.
2-(3-Phenyl-2-propenylthio)-4(3H)-quinazolinone (2). Cinnamyl chloride (3.1 g, 20 mmol) was
added to a solution of compound 1 (4.32 g, 20 mmol) in a mixture of ethanol (80 ml) and water (20 ml) and the
mixture was boiled for 60-70 min. The quinazolinone 2 which crystallized was filtered off, washed with water
heated to 35-40°C (40 ml), and then with ethanol and ether. It was recrystallized from a 4:1 mixture of ethanol
and dioxane.
Reaction of Compound 1 with Ethyl 4-Bromocrotonate 3. A. Compound 1 (1.08 g, 5 mmol) was
added to a mixture of ethanol (30 ml) and water (2 ml) and heated with stirring until the solid dissolved. The
solution was cooled to 10-15°C and kept at that temperature while compound 3 (1.0 g, 6 mmol) was added
dropwise with vigorous stirring. After 20 h the precipitate was filtered off and washed with water and ethanol to
1
give a white microcrystalline substance (1.33 g) which consisted (from the data of H NMR spectroscopy) of
45% of compound 6 and 55% of 3-carboethoxymethyl-2,3-dihydro-5H-thiazolo[2,3-b]quinazolin-5-one (5).
Both compounds were obtained pure by fractional crystallization from ethanol.
B. 1-Carboethoxymethyl-1,2-dihydrothiazolo[3,2-a]quinazol-5-one (6). Compound 1 (1.08 g,
5 mmol) was dissolved in a mixture of ethanol (20 ml) and water (10 ml). Compound 3 (1.0 ml, 6 mmol) was
then added. The mixture was boiled for 1 h, the precipitate which formed was filtered off, washed with water
heated to 30-40°C, and then with ethanol and ether. It was crystallized from ethanol.
a
2-Bromo-6-oxo-1-phenyl-1,2-dihydro-3H,5H-[1,3]thiazino[3,2- ]quinazolinium Tribromide (7a).
A solution of bromine (0.16 ml, 3 mmol) in acetic acid (15 ml) was added dropwise over 30-40 min with
intermittent stirring to a suspension of compound 2 (0.441 g, 1.5 mmol) in glacial acetic acid (35 ml). The
reaction temperature remained at 15-18°C. The orange microcrystalline precipitate which separated over 8-10 h
was filtered off, washed with acetic acid and ether, and dried in a vacuum desiccator over P2O5.
a
2-Iodo-6-oxo-1-phenyl-1,2-dihydro-3H,5H-[1,3]thiazino[3,2- ]quinazolinium Pentaiodide (7b).
Compound 2 (0.441 g, 1.5 mmol) was dissolved on heating in glacial acetic acid (40 ml). The solution was
cooled to 20°C and iodine (1.14 g, 4.5 mmol) in acetic acid (100 ml) was added dropwise over 1 h with
643

intermittent stirring. Stirring was continued for 20-25 h, the brown precipitate was filtered off, washed with
acetic acid and ether, and dried in a vacuum desiccator over P2O5.
a
2-Bromo-1-phenyl-1,2-dihydro-3H-[1,3]thiazino[3,2- ]quinazolin-6-one (8a) and 2-Iodo-1-phenyl-
a
The corresponding salts
and
1,2-dihydro-3H-[1,3]thiazino[3,2- ]quinazolin-6-one (8b).
7a
7b
(2 mmol) were
dissolved in DMSO (25 ml). After solution was complete 20% aqueous sodium acetate (15 ml) was added to the
stirred solution in a water bath (15°C). The precipitate which formed after 1.5-2 h was filtered off and washed
with water. Compound 8b was partially resinified so it was triturated with acetone (30-40 ml) and filtered again.
Both substances were dried in a vacuum desiccator over P2O5.
a
Compound
1-Phenyl-1H-[1,3]thiazino[3,2- ]quinazolin-6-one (9).
8a 8b
or (3 mmol) was dissolved in
morpholine (or piperidine) (10 ml) at 10-15°C.The solution was kept at room temperature for 20 h, then water
(20 ml) was added. The precipitate was filtered off, washed with ethanol and ether, and was then dried in a
vacuum desiccator over P2O5.
a
2-Bromomethyl-1-phenyl-1,2-dihydrothiazolo[3,2- ]quinazolin-5-one (10a) and 2-Iodomethyl-1-
a
phenyl-1,2-dihydrothiazolo[3,2- ]quinazolin-5-one (10b).
8a 8b
Compounds or (3 mmol) was added to a 1:1
mixture of ethanol–DMSO (20 ml), the reaction mixture was boiled for 1.5 h, after which it was cooled and
water (30 ml) was added. After 10-15 h, the precipitate was filtered off and washed with ethanol and ether. Both
products were crystallized from ethanol.
a
Compound
or
2-Methyl-1-phenylthiazolo[3,2- ]quinazolin-5-one (12).
10a
10b
(3 mmol) was added
to a 5% solution of sodium ethoxide (10 ml) and the mixture was kept for 4-5 h, after which water (20 ml) was
added. The precipitate produced over 20 h was filtered off and washed with ethanol and ether. The products
were crystallized from DMF and were then boiled in ethanol to remove DMF.
REFERENCES
1.
K. C. Liu, J. W. Chern, M. H. Yen, and Y. O. Lin, Arch. Pharm., 316, 569 (1983); Chem. Abstr., 99,
88155 (1983).
2.
3.
4.
G. Seybold and B. Wuerzer, Ger. Pat. 3142728; Chem. Abstr., 99, 18106 (1983).
C. Y. Shiau, J. W. Chern, K. C. Liu, C. H. Chan, and M. H. Yen, J. Heterocycl. Chem., 27, 1467 (1990).
L. M. Yun, S. Yangibaev, Kh. M. Shakhidoyatov, V. Ya. Alekseeva, and K. A. V'unov, Khim.
Geterotsikl. Soedin.,254 (1987).
5.
6.
L. I. Giannola, S. Palazzo, L. Lamartina, L. R. Sanseverino, and P. Sabatino, J. Chem. Soc., Perkin
Trans I, 2095 (1986).
M. Gutschow and S. Leistner, Synthesis, 1488 (1995).
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