Synthesis of some functionalized 3-(4-thioxo-3,4-dihydroquinazolin-2-yl) acrylic acid of pharmaceutical interest

Article abstract of DOI:10.1080/714040955

3-(4-Thioxo-3,4-dihydroquinazolin-2-yl)acrylic acid 1 proved to be a convenient precursor for the synthesis of novel polyfunctional quinazoline derivatives of pharmaceutical interest via its treatment with some π-deficient compounds such as phenyl isocyanate and phenyl isothiocyanate. Also, S- and N-glucosidation of quinazoline has been achieved by treatment of 1 with glucopyranosyl bromide in alkaline medium. The behavior of 1 toward acrylonitrile (under Michael reaction condition), paraformaldehyde in the presence of secondary amines (under Mannich reaction condition) and sodium azide were investigated. Moreover, the peptidyl derivatives of quinazoline have been synthesized by condensation of 1 with α-amino acids via different routes. Some of the newly synthesized products were tested for their antimicrobial activities. The structure assignments are based on the analytical and spectroscopic results.

Full text of DOI:10.1080/714040955

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Phosphorus, Sulfur, and Silicon and the Related
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Synthesis of Some Functionalized 3-(4-Thioxo-3,4-
dihydroquinazolin-2-YL) Acrylic Acid of Pharmaceutical
Interest
A. A. Aly a
a Benha University, Benha, Egypt
Published online: 18 Jun 2010.
To cite this article: A. A. Aly (2003) Synthesis of Some Functionalized 3-(4-Thioxo-3,4-dihydroquinazolin-2-YL) Acrylic
Acid of Pharmaceutical Interest, Phosphorus, Sulfur, and Silicon and the Related Elements, 178:11, 2415-2429, DOI:
10.1080/714040955
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Phosphorus, Sulfur, and Silicon, 178:2415–2429, 2003
ꢀC
Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500390235370
SYNTHESIS OF SOME FUNCTIONALIZED
3-(4-THIOXO-3,4-DIHYDROQUINAZOLIN-2-YL)
ACRYLIC ACID OF PHARMACEUTICAL INTEREST
A. A. Aly
Benha University, Benha, Egypt
(Received January 17, 2003; accepted March 26, 2003)
3-(4-Thioxo-3,4-dihydroquinazolin-2-yl)acrylic acid 1 proved to be a
convenient precursor for the synthesis of novel polyfunctional quinazo-
line derivatives of pharmaceutical interest via its treatment with some
π-deficient compounds such as phenyl isocyanate and phenyl isothio-
cyanate. Also, S- and N-glucosidation of quinazoline has been achieved
by treatment of 1 with glucopyranosyl bromide in alkaline medium. The
behavior of 1 toward acrylonitrile (under Michael reaction condition),
paraformaldehyde in the presence of secondary amines (under Mannich
reaction condition) and sodium azide were investigated. Moreover, the
peptidyl derivatives of quinazoline have been synthesized by conden-
sation of 1 with α-amino acids via different routes. Some of the newly
synthesized products were tested for their antimicrobial activities. The
structure assignments are based on the analytical and spectroscopic
results.
Keywords: Antimicrobial activities; peptidyl derivatives; quinazoliny-
lacrylic acid; quinazolinylacryloyl azide, S- and N-glucosides
Quinazoline derivatives and heterocyclic annelated quinazoline con-
tinue to attract great interest due to their diverse pharmacological ac-
tivities. The syntheses and utility of many quinazoline derivatives as
analgesic, antimalarial, diuretic, antitumor, and muscle relaxant have
been reported.1−6 Encouraged by all these facts, and as a continuation of
the investigation on biologically active derivatives among six membered
heterocycles,7−9 I report herein the synthesis of novel heterocyclic com-
pounds containing a quinazoline moiety of anticipated biological and
medicinal importance.
I am grateful to Dr. M. M. Amer, Department of Botany, Faculty of Science, Benha
University for biological screening.
Address correspondence to A. A. Aly, Chemistry Department, Faculty of Science,
Benha University, Benha, Egypt. E-mail: alymaboud@hotmail.com
2415

2416
A. A. Aly
RESULTS AND DISCUSSION
The requisite starting compound 3-(4-thioxo-3,4-dihydroquinazolin-
2-yl)acrylic acid (1) was prepared by reaction of phosphorus pen-
tasulphide with 3-(4-oxo-3,4-dihydroquinazolin-2-yl)acrylic acid.9
Treatment of the quinazolinethione 1 with either phenyl iso-
cyanate or phenyl isothiocyanate in boiling benzene afforded 3-(3-
phenylcarbamoyl/thiocarbamoyl-4-thioxo-3,4-dihydroquinazolin-2-yl)
acrylicacid (2a,b). The readily available 2a,b could be easily de-
hydrated by fusion above its melting point to give the diazepinone
derivatives 3a,b.
Recently, significant progress has been made in the develop-
ment of antiviral chemotherapy due to the discovery of nucleo-
side analogues with potent antiviral activities.10,11 Accordingly, the
glucosidation of quinazolinethione 1 with 2,3,4,6-tetra-O-acetyl-α-
D-glucopyranosyl bromide in alkaline medium affords 3-[4-(2,3,4,6-
tetra-O-acetyl-β-D-glucopyranosylsulfanyl)quinazolin-2-yl]acrylic acid
(4a) in high yield and 3-[4-thioxo-3-(2,3,4,6-tetra-O-acetyl-β-D-
glucopyranosyl)-3,4-dihydroquinazolin-2-yl]acrylic acid (4b) in low
yield. The 1H NMR spectra of compounds 4a and 4b showed the pres-
ence of two doublets at δ 6.26, 6.11 ppm with spin-spin coupling con-
stants 10.89, 10.83 Hz, respectively, that were assigned to H-1ꢁ for 4a
and 4b, which corresponds to a diaxial orientation of H-1ꢁ and H-2ꢁ in-
dicating the presence of only β-configuration12,13 for compounds 4a,b.
Deprotection of the glucoside 4a with methanolic ammonia at
room temperature gave 3-[4-(β-D-glucopyranosylsulfanyl)quinazolin-2-
1
yl]acrylic acid (5). The H NMR spectrum of compound 5 revealed the
presence of a doublet at δ 5.20 ppm with spin-spin a coupling constant
10.13 Hz due to H-1ꢁ corresponding to diaxial orientation of H-1ꢁ and H-
2ꢁ which indicated the presence of only β-D-glucopyranose moiety.12,13
When the quinazolinethione 1 was allowed to react with acrylonitrile
in dry pyridine, it underwent a Michael-type addition to the activated
double bond of the nitrile to give 3-[4-(2-cyanoethylsulfanyl)quinazolin-
2-yl]acrylic acid (6). Interestingly, the attempted alkaline hydroly-
sis of 6 failed to provide the corresponding acid, but resulted in
the cleavage of the cyanoethyl group giving back the starting com-
pound 1. Obviously, a retro Michael reaction had occurred owing
to the presence of a bulky substituted quinazolinyl moiety at the
β-carbon and the use of high temperature under which the reaction
was carried out.14 Moreover, the reaction of quinazolinethione 1 with
paraformaldehyde in the presence of secondary amines (viz piperidine
and morpholine) proceeded smoothly to give the Mannich bases 7a,b,
(Scheme 1).

Thioxodihydroquinazolinylacrylic Acids
2417
SCHEME 1
Recently there has been a growing interest in the area of application
of azides in organic synthesis which could be attributed to the broad
spectrum of reactivity of this versatile reagents.15 Because of this, 3-(4-
thioxo-3,4-dihydroquinazolin-2-yl)-acryloyl azide (8) was synthesized
following the standard method available in the literature.16 Thus, stir-
ring equimolar amounts of the acid chloride and aqueous NaN3 in dry
acetone at 0–5◦C afforded the acid azide 8.
The acid azide 8 was used to add a triazole moiety which is
known to be associated with a broad spectrum of biological action17

2418
A. A. Aly
to quinazoline. Thus, the 1,3-dipolar cycloaddition reaction of acry-
loyl azide 8 with active methylene compounds18 (viz ethyl acetoac-
etate, ethyl cyanoacetate, malononitrile and diethyl malonate) in the
presence of sodium ethoxide afforded the corresponding triazoles 9–12,
(Scheme 2).
SCHEME 2
Finally, the main goal of this study was the utility of the quinazoliny-
lacrylic acid 1 as a building block for the construction of novel quina-
zolines containing different amino acid residues incorporated in an
amide linkage to form peptidyl derivatives of interesting pharmacologi-
cal activities.19−21 Thus, the condensation of 1 with α-amino acid methyl
ester hydrochlorides (viz glycine, DL-alanine and DL-phenylalanine
methyl ester hydrochloride) in tetrahydrofuran containing triethyl
amine and dicyclohexyl carbodiimide22 afforded quinazolinylacryloyl
amino acid methyl esters 13a–c.
The compounds 13a–c were also obtained independently by two other
routes:
(1) Condensation of quinazolinylacryloyl chloride with α-amino acid
methyl ester hydrochlorides in dioxane-Et3N medium.
(2) Coupling of quinazolinylacryloyl azide 8 with α-amino acid methyl
ester hydrochlorides.23

Thioxodihydroquinazolinylacrylic Acids
2419
Hydrazinolysis of methyl [3-(4-thioxo-3,4-dihydroquinazolin-2-yl)-
acryloyl-amino]acetate (13a) in absolute ethanol gave N-hydrazino-
carbonylmethyl-3-(4-thioxo-3,4-dihydroquinazolin-2-yl)acryl amide
(14). The diazotization of 14 in acidic medium gave the corresponding
acid azide 15 which proved to be a versatile building block for new pep-
tides of biological interest via its reaction with α-amino acid methyl
ester hydrochlorides (viz glycine, DL-alanine and DL-phenylalanine
methyl ester hydrochloride) to give the dipeptides 16a–c (Scheme 3).
SCHEME 3

2420
A. A. Aly
Antimicrobial Activity
The antimicrobial activities of some synthesized compounds were tested
in vitro by the filter paper and hole plate method24 against various
pathogenic bacteria, such as Gram +ve bacteria as Bacillus subtilis,
staphlococcus aureus, and Gram −ve bacteria as Escherichia coli, Pseu-
domonas aerginosa in addition to fungi as Aspergillus niger using sul-
phadiazine as a reference standard. The culture medium was normal
nutrient agar (NA) supplemented with 1 g yeast cm3. According to the
solubility of the tested compounds, different polar and nonpolar solvent
were used, a good solubility was shown in 15% acetone (V/V) for all test
compounds. Preliminary tests were carried out to estimate the mini-
mum inhibitory concentration (MIC) of the test compounds. Based on
the previous preliminary test, closely spaced test concentration were
selected, they are (500, 250, 125 µg/ml).
Sulphadiazine was dissolved in filter sterilized 10 ml of 15% acetone
(V/V) and employed in similar concentration as control. The zones of
inhibition were measured in mm and the results are shown in Table I.
The results obtained from the antimicrobial tests showed that com-
pound 1 exhibits a moderate activity against bacteria but is inactive
against fungi. Also, compound 3b, has promising bactericidal activity
but is inactive against Aspergillus niger. But, compounds 4a, 6b, 8, 10,
and 13a showed higher activity against bacteria and fungi. Also, com-
pounds 16a,b have higher activity than the other tested compounds
when compared with the standard drug. These data indicate that the
incorporation of a carbohydrate moiety, a basic mannich side and a pep-
tidyl moiety into quinazolinethione 1 enhances its activity towards the
bacteria and fungi.
TABLE I Antimicrobial Activity
Tested
samples/organisms B. subtilis S. aureus E. coli P. aerginosa A. higer
1
8
10
12
22
18
8
—
12
23
12
12
10
10
18
16
12
12
—
18
21
—
12
15
14
21
15
14
12
16
18
12
—
—
13
16
8
—
—
18
16
—
3b
4a
6b
8
10
13a
16a
16b
Sulphadiazine
10
18
13
10
12
10
15
14
10
Diameter of inhibition zones is measured in nm; (—) = no inhibition.

Thioxodihydroquinazolinylacrylic Acids
2421
In conclusion, the readily obtainable quinazolinylacrylic acid are
valuable precursors for the synthesis a variety of, otherwise not read-
ably obtainable, heteroaromatics and modified peptides of biological
interest.
The structural formulas of all newly synthesized compounds were
elucidated and confirmed by elemental and spectroscopic analysis (cf.
Table II; Experimental).
EXPERIMENTAL
Melting points were taken in open capillary tubes and are uncorrected.
IR spectra in KBr were recorded on a Shimadzu 470 spectrophotmeter
1
and H NMR spectra (CDCl3, DMSO-d6) were recorded on a Varian
Gemini, 200 MHz using TMS as internal reference (Chemical shifts
are expressed as δ, ppm). Mass spectra were obtained on a Shimadzu,
GCMS QP 1000EX mass spectrometer (70 ev EI mode).
TABLE II Physical Data of Compounds (1–7)
Analysis %
Calcd./(Found)
Molecular
Cpd. No. Yield (%) m.p. (◦C)
formula (mol. wt.)
C
H
N
1
68
75
62
41
46
57
7
>300
238–9
261–3
201–3
210–12
261–3
236–8
261–3
197–9
190–2
176–8
C11H8N2O2S
(232.26)
56.88 3.47 12.06
(56.75 3.53 12.19)
61.53 3.73 11.96
2a
2b
3a
3b
4a
4b
5
C
18H13N3O3S
(351.38)
61.63
3.60 11.83)
C
18H13N3O2S2
(367.45)
58.84 3.57 11.44
(58.71 3.69 11.58)
64.85 3.33 12.60
(64.93 3.41 12.69)
61.87 3.17 12.03
(61.75 3.11 12.09)
C18H11N3O2S
(333.36)
C
18H11N3OS2
(349.43)
C
25H26N2O11
(562.55)
S
53.38 4.66
(53.61 4.48
53.38 4.66
(53.49 4.77
51.77 4.60
(51.56 4.71
4.98
4.79)
4.98
4.83)
7.10
7.19)
C
25H26 N2O11
(562.55)
S
62
67
60
62
C17H18N2O7S
(394.40)
C14H11N3O2S
(285.32)
C17H19N3O2S
(329.42)
C16H17N3O3S
(331.39)
6
58.93 3.89 14.73
(58.81 3.80 14.61)
61.98 5.81 12.76
7a
7b
(61.82 5.76
12.83
57.99 5.17 12.68
(57.85 5.23 12.75)

2422
A. A. Aly
3-(4-Thioxo-3,4-dihydroquinazolin-2-yl)acrylic Acid (1)
To a solution of 3-(4-oxo-3,4-dihydroquinazolin-2-yl)acrylic acid9
(10 mmol) in xylene (40 ml), phosphorus pentasulphide (10 mmol) was
added and the reaction mixture was heated under reflux for 1h. The
solid formed after cooling was filtered off and crystallized from ethanol
to give 1. IR: ν = 3450–3260 (OH, NH), 1690 (CO), 1605 (C N) and
1
1285 cm−1 (CS); H NMR (CDCl3): δ = 6.99 (d, 1H, J = 13.67 Hz, β-
olefinic-H), 7.00–7.13 (m, 5H, ArH and α-olefinic-H), 9.10 (s, 1H, NH
exchangeable), 11.93 (s, 1H, OH, exchangeable).
3-(3-Phenylcarbamoyl/thiocarbamoyl-4-thioxo-3,
4-dihydroquinazolin-2-yl)acrylic Acid (2a,b)
General Procedure
A mixture of quinazolinethione 1 (5 mmol) and phenyl isocyanate or
phenyl isothiocyanate (5 mmol) in dry benzene (30 ml) was refluxed for
3 h. The excess of benzene was distilled under reduced pressure, the
separated product was filtered and crystallized from ethanol to afford
2a,b. IR: ν = 3450–3200 (OH, NH) 1690, 1675–1670 (CO) and 1289 cm−1
1
(CS); H NMR of 2b (DMSO-d6): δ = 6.97 (d, 1H, J = 13.66 Hz, β-
olefinic-H) 6.99–7.48 (m, 10H, ArH and α-olefinic-H), 10.22 (s, 1H, NH
exchangeable), 12.1 (s, 1H, OH exchangable).
9-Phenyl-8,9,10,11-tetrahydro-11-thioxo-5,9,10a-
triazacyclohepta[b]naphthalene-8,10-dione (3a) and
9-Phenyl-8,9,10,11-tetrahydro-10,11-dithioxo-5,9,10a-
triaza-cyclohepta[b]naphthalen-8-one (3b)
The quinazoline derivatives 2a or 2b (4 mmol) were heated in a fusion
tube provided with an air condenser above their melting points on a
sand bath for 2 h. The solid product which formed after cooling crystal-
lized from ethanol to give 3a,b. IR: ν = 1670–1660 (CO), 1296 (CS of
3b). The absence of any absorption bands due to OH or NH, confirmed
1
the cyclization process; H NMR (CDCl3) of 3a: δ = 6.88 (d, 1H, J =
13.68 Hz, β-olefinic-H) 6.90–7.35 (m, 10H, ArH and α-olefinic-H); MS
of 3a m/z (%) 333 (56.6) and MS of 3b: m/z (%) 349 (79.8).
3-[4-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosylsulfanyl)-
quinazolin-2-yl]acrylic acid (4a) and 3-[4-Thioxo-3-
(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3,4-
dihydroquinazolin-2-yl]acrylic Acid (4b)
To a solution of 1 (5 mmol) in a mixture of (20 ml) DMF and aq.
K2CO3 (5 mmol) in (15 ml) H2O, was added 2,3,4,6-tetra-O-acetyl-α-D-

Thioxodihydroquinazolinylacrylic Acids
2423
glucopyranosyl bromide (9 mmol) in (15 ml) DMF dropwise with stirring
at room temperature for 30 min. Stirring was continued overnight until
the starting material was consumed (TLC). The reaction mixture was
cooled and poured on ice/cold water. The solids obtained was filtered off
and chromatographed on a column of silica gel (petroleum ether/ethyl
acetate, 3:1, v/v) to give 4a,b. IR: ν = 3405 (OH), 1735–1730 (CO of
acetyl), 1690 (CO of acid); 1H NMR of 4a (CDCl3): δ = 1.80, 1.91, 1.97,
2.08 (4 s, 12H, 4Ac), 3.97–4.21 (m, 2H, H-6ꢁ, H-5ꢁ), 4.81–5.36 (m, 3H,
H-4ꢁ, H-2ꢁ, H-3ꢁ), 6.26 (d, 1H, J = 10.89 Hz, H-1ꢁ), 6.99 (d, 1H, J =
13.65 Hz, β-olefinic-H), 7.01–7.75 (m, 5H, ArH and α-olefinic-H), 11.98
1
(s, 1H, OH, exchangeable); MS of 4a: m/z (%) 562 (81.51); H NMR of
4b (CDCl3): δ = 1.83, 1.95, 2.06, 2.11 (4 s, 12H, 4Ac), 3.91–4.29 (m, 2H,
H-6ꢁ, H-5ꢁ), 5.10–5.32 (m, 3H, H-4ꢁ, H-2ꢁ, H-3ꢁ), 6.11 (d, 1H, J = 10.83
Hz, H-1ꢁ), 6.97 (d, 1H, J = 13.66 Hz, β-olefinic-H), 7.11-8.21 (m, 5H,
ArH and β-olefinic-H).
3-[4-(β-D-glucopyranosylsulfanyl)quinazolin-2-yl]acrylic
Acid (5)
To a suspension of compound 4a (4 mmol) in absolute methanol (20
ml), a saturated solution of ammonia in absolute methanol (20 ml)
was added. The reaction mixture was stirred at room temperature
for 1 h. and left overnight in refrigerator until the starting mate-
rial was consumed (TLC). The solvent was evaporated under reduced
pressure and the residue was purified over a column of silica gel
(chloroform/methanol, 5:1, v/v) to afford 5. IR: ν = 3450–3210 (OH),
1
1691 (CO); H NMR (CDCl3) δ = 3.26 (m, 3H, H-6ꢁ, H-6ꢁ, H-5ꢁ), 3.36
(m, 1H, H-4ꢁ), 3.52 (m, 2H, H-3ꢁ, H-2ꢁ), 4.11 (t, 1H, J = 6.16 Hz,
HO-6ꢁ), 4.82 (d, 1H, J = 6.11 Hz, HO-4ꢁ), 5.14 (d, 1H, J = 6.10 Hz,
HO-3ꢁ), 5.20 (d, 1H, J = 10.13 Hz, H-1ꢁ), 5.31 (d, 1H, J = 5.88 Hz,
HO-2ꢁ), 6.96 (d, 1H, J = 13.65 Hz, β-olefinic-H) 6.98–7.81 (m, 5H, ArH
and α-olefinic-H), 11.87 (s, 1H, OH, exchangeable); MS: m/z (%) 394
(28.66).
3-[4-(2-Cyanoethylsulfanyl)quinazolin-2-yl]acrylic
Acid (6)
Compound 6 was prepared according to the published procedure,25 and
was crystallized from benzene. IR: ν = 3490–3300 (OH), 2225 (C N),
1690 (CO), 1290 cm−1 (CS); 1H NMR (CDCl3): δ = 2.96 (t, 2H, J = 7.34
Hz, CH2CN), 3.79 (t, 2H, J = 7.45 Hz, CH2S), 6.89 (d, 1H, J = 13.66
Hz, β-olefinic-H) 6.92-7.84 (5H, ArH and α-olefinic-H), 12.12 (s, 1H, OH
exchangeable).

2424
A. A. Aly
3-[(3-Piperidin-1-yl/morpholin-4-yl)methyl-4-thioxo-3,4-
dihydroquinazolin-2-yl]acrylic acid (7a,b)
A mixture of 1 (5 mmol), formaldehyde solution in water (5 ml) and
secondary amines (10 mmol) in ethanol (25 ml) was refluxed for 6 h. The
reaction mixture was concentrated and the solid formed after cooling
was filtered and crystallized from methanol to give 7a,b. IR: ν = 3480–
3320 (OH), 1690–1685 (CO), 1295 (CS); 1H NMR of 7a (CDCl3): δ = 1.46
(m, 6H, 3 CH2), 2.62 (m, 4H, CH2NCH2), 5.09 (s, 2H, CH2), 6.88 (d, 1H,
J = 13.66 Hz, β-olefinic-H) 6.91–7.89 (m, 5H, ArH and α-olefinic-H),
12.3 (s, 1H, OH, exchangeable), 1H NMR of 7b (CDCl3) δ = 2.77 (m, 4H,
CH2NCH2), 3.63 (m, 4H, CH2OCH2), 5.21 (s, 2H, CH2), 6.92 (d, 1H, J =
13.66 Hz, β-olefinic-H) 6.94–7.98 (m, 5H, ArH and α-olefinic-H), 11.86
(s, 1H, OH, exchangeable).
3-(4-Thioxo-3,4-dihydroquinazolin-2-yl)acryloyl azide (8)
A saturated solution of sodium azide in water16 (8 mmol) was added
dropwise to a stirred solution of 3-(4-thioxo-3,4-dihydroquinazolin-2-
yl)acryloyl chloride (4 mmol) in dry acetone (20 ml) at 0–5◦C. The mix-
ture was stirred for further 30 min. The reaction mixture was added to
crushed ice and the precipitated product was filtered to give the azide 8,
yield (73%), m.p: 120–3◦C (with decomposition). IR: ν = 2170 (CON3),
1295 cm−1 (CS).
Reaction of acryloyl azide 8 with active methylene
compounds: Formation of compounds 9–12
General Procedure
A solution of Na (0.15 g) in absolute ethanol (20 ml) is added in
one portion to an ice-cold solution of compound 8 (5 mmol) in abso-
lute ethanol (20 ml) and the active methylene compounds (10 mmol).
The mixture was stirred overnight. Then the solvent was evaporated
in vacuo, the concentrated ethanol solution was poured into ice-cold
water and the corresponding product was collected by filtration and
crystallized from ethanol to give the compounds 9–12.
Ethyl 5-methyl-1-[3-(4-thioxo-3,4-dihydroquinazolin-
2-yl)acryloyl]-1H-1,2,3-triazole-4-carboxylate (9)
Prepared from 8 and ethyl acetoacetate; yield: 81% m.p: 151–153◦C;
Anal. Calcd. for C17H15N5O3S (369.40):C, 55.27; H, 4.09; N, 18.96%;
Found: C, 55.20; H, 4.18; N, 18.83; IR: ν = 3290 (NH), 1730, 1670 (CO),

Thioxodihydroquinazolinylacrylic Acids
2425
1610 (CN), 1297 cm−1 (CS); 1H NMR (DMSO-d6) : δ = 1.27 (t, 3H, J =
8.11 Hz, CH3), 2.11 (s, 3H, CH3), 3.96 (q, 2H, J = 8.11 Hz, CH2), 6.99 (d,
1H, J = 13.67 Hz, β-olefinic-H) 7.00–7.38 (m, 5H, ArH and α-olefinic-H),
9.21 (s, 1H, NH, exchangeable); MS: m/z (%) 369 (83.2).
Ethyl 5-amino-1-[3-(4-thioxo-3,4-dihydroquinazolin-2-yl)-
acryloyl]-1H-1,2,3-triazole-4-carboxylate (10)
Prepared from 8 and ethyl cyanoacetate; yield: 65%; m.p.: 163–165◦C;
Anal. Calcd. for C16H14N6O3S (370.39): C, 51.88; H, 3.81; N, 22.69%;
Found: C, 51.97; H, 3.70; N, 22.60; IR: ν = 3350–3260 (NH), 1731, 1675
(CO), 1291 cm−1 (CS); 1H NMR (DMSO-d6): δ = 1.31 (t, 3H, J = 8.12 Hz,
CH3), 4.13 (q, 2H, J = 8.12 Hz, CH2), 4.97 (br, 2H, NH2), 7.02 (d, 1H, J
= 13.65 Hz, β-olefinic-H) 7.04–8.11 (m, 5H, ArH and α-olefinic-H), 9.32
(s, 1H, NH, exchangeable); MS: m/z (%) 370 (78.5).
5-Amino-1-[3-(4-thioxo-3,4-dihydroquinazolin-2-yl)-
acryloyl]-1H-1,2,3-triazole-4-carbonitrile (11)
Prepared from 8 and malononitrile; yield: 86%, m.p.: 140–142◦C; Anal.
Calcd. for C14H9N7OS (323.33): C, 52.01, H, 2.81; N, 30.33%; Found:
C, 52.17; H, 2.68; N, 30.47; IR: ν = 3380–3250 (NH); 2226 (C N), 1671
(CO), 1290 cm−1 (CS); 1H NMR (DMSO-d6): δ = 5.1 (br, 2H, NH2), 6.88
(d, 1H, J = 13.65 Hz, β-olefinic-H) 6.90–7.93 (m, 5H, ArH and α-olefinic-
H), 9.25 (s, 1H, NH, exchangeable).
Ethyl 5-oxo-1-[3-(4-thioxo-3,4-dihydroquinazolin-2-yl)-
acryloyl]-4,5-dihydro-1H-1,2,3-triazole-4-carboxylate (12)
Prepared from 8 and diethyl malonate, yield: 71%; m.p.: 170–172◦C;
Anal. Calcd. for C16H13N5O4S (371.37): C, 51.75; H, 3.53; N, 18.86%;
Found: C, 51.82; H, 3.65; N, 18.72; IR: ν = 3210 (NH), 1732, 1710, 1670
(CO), 1293 cm−1 (CS); MS: m/z (%) 371 (97.1).
General Procedure for Preparation of Acryloyl Amino
Acid Methyl Esters 13a–c
Method A
To a solution of the α-amino acid methyl ester hydrochlorides
(7 mmol) in tetrahydrofuran (50 ml) was added triethylamine (3 ml).
The solution was kept for 25 min at 0–5◦C and the precipitated triethy-
lamine hydrochloride was filtered off. To the filtrate at −5◦C was added
the quinazolinylacrylic acid 1 (5 mmol) and dicylohexyl-carbodiimide

2426
A. A. Aly
(5 mmol). The reaction was allowed to proceed for 3 h at 0◦C; for 3 h
at 5◦C and for 24 h at room temperature. The dicyclohexylurea was
removed by filteration and the solvent evaporated to dryness under re-
duced pressure. The residual solid was recrystallized from ethanol to
give 13 a–c
Method B
Quinazolinylacryloyl chloride (5 mmol) was dissolved in dioxane
(40 ml) containing (3 ml) triethylamine and added to a solution of the
α-amino acid methyl ester hydrochlorides (7 mmol). The reaction mix-
ture was stirred at room temperature for 30 min followed by refluxing
for (2–3 h) until completion of the reaction (TLC). After cooling of the
reaction mixture, the Et3N·HCl was filtered off and a benzeneether mix-
ture (1:1) (100 ml) was added. The reaction mixture washed with 10%
NaHCO3 and dried over anhydrous Na2SO4. Evaporation of the solvent
under vacuum gave the solid products 13a–c.
Method C
To a solution of acryloyl azide 8 (5 mmol) in ethyl acetate was added
α-amino acid methyl ester hydrochlorides (7 mmol) and triethylamine
(3 ml). The reaction mixture was stirred for 6 h at 4◦C and for 12 h
at room temperature. Then the reaction mixture was washed with 0.5
N HCl, NaHCO3 and dried over anhydrous Na2SO4. The solution was
evaporated under vacuum to dryness and the residual material was
recrystallized to give compounds 13a–c.
Methyl [3-(4-thioxo-3,4-dihydroquinazolin-2-yl)-
acryloylamino]acetate (13a)
Yield: 67%; m.p.: 173–175◦C; Anal. Calcd. for C14H13N3O3S (303.34):
C, 55.43; H, 4.32; N, 13.85%; Found C, 55.51; H, 4.45; N, 13.93; IR: ν =
3320–3290 (NH), 1730 (CO of ester), 1680–1675 (CO of amide), 1290
1
cm−1 (CS); H NMR (CDCl3): δ = 2.82 (s, 3H, CH3), 3.51 (d, 2H, CH2),
6.98 (d, 1H, J = 13.68 Hz, β-olefinic-H) 6.99–7.39 (m, 5H, ArH and
α-olefinic-H), 9.20, 9.31 (2s, 2H, 2NH, exchangeable); MS: m/z (%) 303
(81).
Methyl 2-[3-(4-thioxo-3,4-dihydroquinazolin-2-yl)-
acryloylamino]propanoate (13b)
Yield 63%; m.p.: 186–188◦C; Anal. Calcd. for C15H15N3O3S (317.36):
C, 56.77; H, 4.76; N, 13.24%; Found : C, 56.82; H, 4.89; N, 13.35; IR:
ν = 3295–3200 (NH), 1732 (CO of ester), 1675–1670 (CO of amide),

Thioxodihydroquinazolinylacrylic Acids
2427
1
1301 cm−1 (CS); H NMR (CDCl3): δ = 1.23 (d, 3H, CH3), 2.80 (s, 3H,
CH3), 4.11–4.16 (m, 1H, CH), 6.92 (d, 1H, J = 13.67 Hz, β-olefinic-
H) 6.91–7.41 (m, 5H, ArH and α-olefinic-H), 9.24, 9.35 (2s, 2H, 2NH,
exchangeable).
Methyl 2-[3-(4-thioxo-3,4-dihydroquinazolin-2-yl)-
acryloylamino]-3-phenylpropanoate (13c)
Yield: 71%; m.p. 161–163◦C; Anal. Calcd. for C21H19N3O3S (393.46): C,
64.10; H, 4.87; N, 10.68%; Found: C, 64.20; H, 4.75; N, 10.52; IR: ν =
3350–3260 (NH), 1728 (CO of ester), 1680–1670 (CO of amide), 1286
1
cm−1 (CS); H NMR (CDCl3): δ = 2.81 (s, 3H, CH3), 2.99 (d, 2H, CH2),
4.03–4.15 (m, 1H, CH), 6.89 (d, 1H, J = 13.66 Hz, β-olefinic-H) 6.90–7.39
(m, 5H, ArH and α-olefinic-H), 9.12, 9.26, (2s, 2H, 2NH, exchangeable);
MS : m/z (%) 393 (76).
N-Hydrazinocarbonylmethyl-3-(4-thioxo-3,4-
dihydroquinazolin-2-yl)acryl Amide (14)
To a solution of 13a (5 mmol) in ethanol (30 ml) was added hydrazine hy-
drate (2 ml). The reaction mixture was kept for 24 h at 0–5◦C. The solid
which separated was crystallized from ethanol to give the hydrazide
14. Yield: 60; m.p.: 216–268◦C; Anal. Calcd. for C13H13N5O2S (303.34):
C, 51.47; H, 4.32; N, 23.09%; Found: C, 51.31; H, 4.41; N, 23.18%; IR:
ν = 3210–3195 (NH), 1680–1670 (CO), 1615 (CN), 1287 cm−1 (CS), 1H
NMR (CDCl3) δ = 3.31 (d, 2H, CH2), 4.91 (br, 2H, NH2), 7.02 (d, 1H, J =
13.65 Hz, β-olefinic-H) 7.03–7.85 (m, 5H, ArH and α-olefinic-H), 9.21,
9.29, 9.32, (3s, 3H, 3NH, exchangeable).
General Procedure for the Preparation of the Dipeptide
Derivatives 16a–c
The hydrazide 14 (7 mmol) was dissolved in a mixture of 8 ml acetic
acid, 4 ml 5N HCl and 10 ml water, the solution was cooled to 0◦C,
and the solution of 0.5 g of sodium nitrite in (4 ml) water was added
dropwise over 10 min and the reaction was allowed to proceed for 10 min
at 0◦C. The acid azide 15 was precipitated as a syrup which was taken
up in (50 ml) cold ethyl acetate. The ethyl acetate layer was washed
with cold 3% NaHCO3 and briefly dried over anhydrous Na2SO4. The
solution of azide 15 was added to 8 mmol of α-amino acid methyl ester
hydrochlorides in (20 ml) ethyl acetate containing (4 ml) Et3N and the
reaction mixture was stirred for 6 h at 4◦C and for another 12 h at room
temperature. The reaction mixture washed with 0.5N HCl, NaHCO3

2428
A. A. Aly
and dried over anhydrous Na2SO4. The solution was evaporated under
vacuum to dryness and the residual material crystallized from benzene
to give the dipeptide derivatives 16a–c.
Methyl 2-{2-[3-(4-thioxo-3,4-dihydroquinazolin-2-yl)-
acryloylamino]acetylamino}-acetate (16a)
Yield: 55%; m.p.: 164–166◦C; Anal. Calcd. for C16H16N4O4S (360.39): C,
53.32; H, 4.47; N, 15.55%; Found: C, 53.41; H, 4.56; N, 15.67; IR: ν =
3310–3200 (NH), 1730 (CO of ester), 1679–1670 (CO of amides), 1296
cm−1 (CS); 1H NMR (DMSO-d6) δ = 2.82 (s, 3H, CH3), 3.12 (d, 2H, CH2),
3.46 (d, 2H, CH2), 7.00 (d, 1H, J = 13.63 Hz, β-olefinic-H) 7.01–7.52 (m,
5H, ArH and α-olefinic-H), 9.19, 9.22, 9.32 (3s, 3H, 3NH, exchangeable);
MS: m/z (%) 360 (78.2).
Methyl 2-{2-[3-(4-thioxo-3,4-dihydroquinazolin-2-yl)-
acryloylamino]acetylamino}-propanoate (16b)
Yield: 51%; m.p.: 183–185◦C; Anal. Caled. for C17H15N4O4S (374.42):
C, 54.53; H, 4.85; N, 14.96%; Found: C, 54.66; H, 4.98; N, 14.81; IR:
ν = 3290–3200 (NH), 1731 (CO of ester), 1675–1670 (CO of amides),
1290 cm−1 (CS); MS: m/z (%) 374 (83.22).
Methyl 2-{2-[3-(4-thioxo-3,4-dihydroquinazolin-2-yl)-
acryloylamino]acetylamino}-3-phenylpropanoate (16c)
Yield: 56%; m.p.: 190–192◦C; Anal. Calcd. for C23H22N4O4S (450.51):
C, 61.32; H, 4.92; N, 12.44%; Found: C, 61.41; H, 4.85; N, 12.51; IR:
ν = 3285–3195 (NH), 1729 (CO of ester), 1680–1670 (CO of amides),
1294 cm−1 (CS); 1H NMR (DMSO-d6) δ = 2.82 (s, 3H, CH3), 2.91 (d, 2H,
CH2), 4.10–4.17 (m, 1H, CH), 6.96 (d, 1H, J = 13.64 Hz, β-olefinic-H)
6.98–7.41 (m, 5H, ArH and α-olefinic-H), 9.20, 9.24, 9.34 (3s, 3H, 3NH,
exchangeable); MS: m/z (%) 450 (65.32).
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