Synthesis and antifungal activity of some new quinazoline and benzoxazinone derivatives

Article abstract of DOI:10.1002/1521-4184(200011)333:11<365::AID-ARDP365>3.0.CO;2-2

The hitherto unknown 2-isopropyl-6,8-dibromo-4H-3,1-benzoxazin-4-one (2) was subjected to condensation with either primary or secondary amines affording the benzamide derivatives (3-7), while with alcohols in presence of the base, corresponding esters were obtained (8 and 9). Acylation of the hydrazide (12) or its cyclized form (13) gave (14-17). The quinazolinone derivative (18) was obtained either when (12) was reacted with nitrous acid or via fusion of (2) with ammonium acetate. The thione (20) which was obtained via reaction of (18) with Lawesson's reagent, was subjected to either alkylation yielding (21-25) or desulphurization with primary amines affording (26 and 27). Treatment of (18) as well as (20) with a chlorinating agent provided (29, 30) and (28, 29) mixtures, respectively. Ten of our compounds were examined against Sclerotium cepivorum as well as Botrytis allii on PDA media. These compounds showed a significant reduction of mycelial growth and scleratia number of these fungi which cause the white rot and neck rot diseases of onion.

Full text of DOI:10.1002/1521-4184(200011)333:11<365::AID-ARDP365>3.0.CO;2-2

New Quinazoline and Benzoxazinone Derivatives
365
Synthesis and Antifungal Activity of Some New Quinazoline and
Benzoxazinone Derivatives
Alyaa A. Shalaby*, Abdel Momen A. El-Khamry, S.A. Shiba, and Abdel Aal Alm Eldeen Abdalah Ahmed
Chemistry Department, Faculty of Science, Ain Shams University, Abbassia, Cairo, Egypt
Awaref A. Hanafi
Plant Pathology Research Institute, Agriculture Research Center, Giza, Egypt
Key Words: Antifungal activity; quinazoline derivatives; benzoxazinone derivatives
Summary
The hitherto unknown 2-isopropyl-6,8-dibromo-4H-3,1-benzox-
azin-4-one (2) was subjected to condensation with either primary
or secondary amines affording the benzamide derivatives (3–7),
while with alcohols in presence of the base, corresponding esters
were obtained (8 and 9). Acylation of the hydrazide (12) or its
cyclized form (13) gave (14–17). The quinazolinone derivative
(18) was obtained either when (12) was reacted with nitrous acid
or via fusion of (2) with ammonium acetate. The thione (20) which
was obtained via reaction of (18) with Lawesson’s reagent, was
subjected to either alkylation yielding (21–25) or desulphurization
with primary amines affording (26 and 27). Treatment of (18) as
well as (20) with a chlorinating agent provided (29, 30) and (28,
29) mixtures, respectively. Ten of our compounds were examined
against Sclerotium cepivorum as well as Botrytis allii on PDA
media. These compounds showed a significant reduction of my-
celial growth and scleratia number of these fungi which cause the
white rot and neck rot diseases of onion.
provided the expected benzamide derivatives (3–5)
(Scheme 1). With secondary amines in 1,4-dioxane, ben-
Introduction
The pronounced biological and pharmacological activities zoxazinone (2) yielded the expected products (6 and 7).
of benzoxazinone and quinazolinone derivatives, such as
However, when the reaction was carried out in ethanol the
unexpected ethyl 3,5-dibromo-2-isobutyroylaminobenzoate
(8) was obtained as the only product, which means that
piperidine or morpholine acts as a base favouring the forma-
[1–3]
[4]
[4,5]
anticonvulsant
analgesic and anti-inflammatory
and antifungal
, antihistaminic , antihypertensive
, antimicrobial
, have stimulated these authors to synthe-
,
[6,7]
[8–11]
[12]
size some new derivatives of these classes of compounds with
the hope of obtaining new structures with enhanced potency
or of finding new applications.
Table 1. 13C-NMR of compound (5).
Also we aimed to incorporate a sterically bulky group such
as an isopropyl group in position-2 to detect its role in the
nature and ease of reaction of these compounds.
——————————————————————————————
Results and Discussion
No. of
carbon
δ (ppm)
No. of
carbon
δ (ppm)
Chemistry
——————————————————————————————
C-1
C-2
C-3
C-4
C-5
C-6
C-7
C-8
19.1
33.9
C-9
133.8
164.9
42.4
138.9
127.2
128.2
126.7
The hitherto unknown 6,8-dibromo-2-isopropyl-(4H)-3,1-
benzoxazin-4-one (2) as a key starting compound has been
obtained in fairly good yield by cyclization of 3,5-dibromo-
2-isobutyroylaminobenzoic acid (1) which is obtained by
condensation of 3,5-dibromoanthranilic acid with isobutyr-
oyl chloride in pyridine (Scheme 1).
C-10
C-11
C-12
C-13
C-14
C-15
175.2
138.9
119.5
138.8
124.8
130.2
[13]
[8,14]
According to Ismail
and El-Khamry
the ami-
——————————————————————————————
nolysis of benzoxazinone (2) with primary amines in ethanol
Arch. Pharm. Pharm. Med. Chem.
© WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0365-6233/00/1111/0365 $17.50 +.50/0

366
Shalaby and co-workers
Table 2. 13C-NMR of compound (7).
Table 4. 13C-NMR of compound (12).
——————————————————————————————
——————————————————————————————
No. of
carbon
δ (ppm)
No. of
carbon
δ (ppm)
No. of
carbon
δ (ppm)
No. of carbon
δ (ppm)
——————————————————————————————
——————————————————————————————
C-1
C-2
C-3
C-4
C-5
C-6
19.4
35.4
175.9
138.9
119.7
135.9
C-7
C-8
C-9
C-10
C-11
C-12
123.4
129.0
132.9
166.2
42.1
C-1
C-2
C-3
C-4
C-5
C-6
20.2
20.4
31.6
163.1
138.9
119.6
C-7
C-8
C-9
C-10
C-11
140.8
124.3
128.8
132.9
160.6
66.5
——————————————————————————————
——————————————————————————————
Table 5. 13C-NMR of Compound (13).
tion of ethoxide ion which promotes ring opening of (2) to
give the ester (8) (Scheme 1). This observation is supported
by the reaction of (2) with ethanol and/or n-butanol in the
presence of pyridine as a base to give the esters (8 and 9),
respectively (Scheme 1). The structures of (3–9) have been
confirmed by their analytical data as well as spectroscopic
1
data IR, H-NMR, MS (Tables 6 and 7) and
13
C-NMR data for compounds (5) and (7) (Tables 1 and 2).
——————————————————————————————
On condensation of 2 with ethanolamine at elevated tem-
perature (ca. 170 °C), the expected aminolysis is favoured
over ester formation, giving the quinazoline derivative (10)
which is converted into the corresponding chloro derivative
(11) by treatment with thionyl chloride (Scheme 1). The
structures of (10) and (11) were established by elemental
No. of
carbon
δ (ppm)
No. of
carbon
δ (ppm)
——————————————————————————————
C-1
C-2
C-3
C-4
C-5
C-6
20.1
21.3
31.5
160.9
143.7
119.1
C-7
C-8
C-9
C-10
C-11
140.2
124.1
128.4
128.9
159.1
1
analysis, IR, H-NMR, and MS spectra (Tables 6 and 7), and
13
C-NMR data for compound (11) (Table 3).
Table 3. 13C-NMR of compound (11).
——————————————————————————————
Furthermore, boiling of (12) in n-butanol gave (13) in quan-
titative yield. The structures of (12) and (13) were confirmed
1
by elemental analysis and spectral data; IR, H-NMR, and
13
MS spectra (Tables 6 and 7), beside C-NMR for com-
pounds (12) and (13), (Tables 4 and 5).
The structures of (12) and (13) were further supported by
the following chemical proofs:
——————————————————————————————
No. of
carbon
δ (ppm)
No. of
carbon
δ (ppm)
– Acetylation of (12) and or (13) with acetyl chloride gave
the corresponding acetyl derivatives (14) and (15), respec-
tively, in fairly good yield. Also, cyclization of (14) by
heating at its melting point and/or refluxing with phospho-
rus oxychloride afforded (15) in quantitative yield
(Scheme 1).
——————————————————————————————
C-1
C-2
C-3
C-4
C-5
C-6
21.2
32.6
160.9
143.9
119.4
140.9
C-7
C-8
C-9
C-10
C-11
C-12
123.9
129.9
128.7
162.3
41.6
– Condensation of (12) and/or (13) with p-anisaldehyde
yielded the corresponding Schiff’s bases (16) and (17),
respectively. Cyclization of (16) gave (17) quantitatively
(Scheme 1).
45.5
——————————————————————————————
On the other hand, treatment of (2) with hydrazine hydrate
in ethanolic solution either at room temperature or at 0 °C
afforded a mixture ofthe hydrazide derivative (12) and3-ami-
noquinazolinone derivative (13), while in boiling ethanol or
heating both without solvent at ca. 170 °C, the cyclized form
(13) was obtained as a sole product in good yield (Scheme 1).
[15]
– Nitrosation
of (12) and/or (13) with nitrous acid at
0 °C afforded the same product 6,8-dibromo-2-iso-
propylquinazolin-4-one (18) (Scheme 1).
– Addition of (12) to carbon disulphide in alkaline medium
yielded oxadiazole derivative (19) (Scheme 1).
Arch. Pharm. Pharm. Med. Chem. 333, 365–372 (2000)

New Quinazoline and Benzoxazinone Derivatives
367
Table 6. Characterization data of compounds prepared a)
.
——————————————————————————————————————————————————————————
Compd.
Mp °C
Yield %
Molecular Formula
IR cm–1
No.
(colour)
(solvent)
(M.Wt)
νNH,OH
νC=O
νC=S
——————————————————————————————————————————————————————————
1
198–200
colourless
60–62
85
(E)
78
C11H11Br2NO3
(365.02)
3280
–
1710,1660
1773
–
2
pale yellow
(Pa)
C11H9Br2NO2
–
(347.01)
3
277–278
colourless
289–290
colourless
249–250
colourless
205–207
colourless
198–200
colourless
130–132
colourless
98–100
60
(T)
76
(T+E)
94
(M)
82
(Pb)
85
(Pb)
75
(Pc)
78
(Pb)
60
(Pc)
70
(Pb)
65
(Pb)
25
(Pa)
80
(T+E)
65
(Pb)
70
(T+M)
75
(T+E)
90
(E)
75
(T+E)
92
(Pb)
72
(Pa)
63
(Pa)
54
(Pa)
60
(T)
65
(T)
45
(Pb)
52
(T)
65
C18H18Br2N2O3
(470.16)
C17H15Br2ClN2O2
(474.58)
C18H18Br2N2O2
(454.16)
C16H20Br2N2O2
(432.15)
3282
1650
–
4
3210,3160 1660
3280 1660
–
5
–
6
3210,3180 1690
3210,3160 1670
–
7
C15H18Br2N2O3
(434.13)
–
8
C
13H15Br2NO3
3220
3275
3470
–
1720
1725
1660
1650
–
(393.07)
C15H19Br2NO3
(421.13)
C13H14Br2N2O2
(390.07)
9
–
colourless
139–140
colourless
115–117
yellow
10
11
12
13
14
15
16
17
18
19
20
22
23
24
26
27
28
29
30
31
–
C
13H13Br2ClN2O
–
(408.52)
C11H13Br2N3O2
(379.05)
C11H11Br2N3O
(361.04)
C13H15Br2N3O3
(421.09)
C13H13Br2N3O2
(403.07)
C19H19Br2N3O3
(497.18)
C19H17Br2N3O2
(479.17)
C11H10Br2N2O
(346.02)
C12H11Br2N3O2S
(421.11)
C11H10Br2N2S
(362.08)
C13H14Br2N2S
(390.14)
C18H16Br2N2S
(452.21)
C15H16Br2N2O2S
(448.17)
C15H19Br2N3
(401.14)
C18H17Br2N3
(435.16)
C11H9Br2ClN2S
(396.53)
160–162
colourless
139–140
pale yellow
259–260
colourless
198–200
colourless
280–282
colourless
160–162
pale yellow
268–270
colourless
238–240
colourless
218–220
yellow
3320,3280 1665
3330,3280 1660
3220,3180 1660
3470,3210 1680,1660
3250,3180 1670
–
–
–
–
–
–
1670
1680
–
3160
–
3260,3110 1665
1230
3170
–
–
1230
60–62
colourless
90–92
colourless
80–82
–
–
–
–
–
–
1725
–
colourless
190–192
pale yellow
170–172
pale yellow
180–182
yellow
150–152
pale yellow
255–257
pale yellow
210–212
colourless
3210
3160
3120
–
–
–
–
–
–
1220
C11H8Br2Cl2N2
(398.91)
C11H9Br2ClN2O
(380.47)
C11H10Br2N2O2
(362.02)
–
–
–
–
3220
1670
(Pb)
80
(Pb+T)
br.3350–3300,3210 1670
————————————————————————————————————————————————————————
E = Ethanol, T = Toluene, M = Methanol, Pa = Petroleum ether 40–60 °C, Pb = Petroleum ether 80–100°C, Pc = pet-ether 60–80 °C.
a) Elemental analyses were correct to within ±0.4%.
Arch. Pharm. Pharm. Med. Chem. 333, 365–372 (2000)

368
Shalaby and co-workers
Table 7. 1H-NMR and MS data of prepared compounds.
—————————————————————————————————————————————————————————————–
Compd. 1H-NMR (δ in ppm)
MS (m/z %)
no.
—————————————————————————————————————————————————————————————–
1a
2a
5b
7a
8a
1.22 [d (J = 7), 6H], ≈ at 2.65 (m,1H), 7.88 [d (J = 2), 1H],
7.97 [d(J = 2), 1H] and 9.08 (s, 1H).
–
1.32 [d(J = 7), 6H], ≈ at 2.91 (m,1H), 8.10 [d(J = 2),1H]] and
8.10 [d(J = 2), 1H]
–
1.1 [d(J = 7), 6H], 2.58 (m, 1H), 4.38 (d,2H), 7.29 (m,5H),
7.65 [d(J = 2), 1H], 8.05 [d(J = 2),1H], 8.80 (t,1H) and 9.55 (s,1H).
[M–H2O] (436,9.62%), 421 (7.82%), 393 (2.11%),
345 (16.45%), 91 (100%).
1.22 [d(J = 7), 6H], 2.61 [m, 1H], 3.52 (m, 4H), 3.82 (m, 4H),
7.27 [d(J = 2), 1H], 7.68 [d(J = 2), 1H] and 8.28 (sbr., 1H).
[M+2]+ (434,23%), 348 (83.71%), 277 (33.68%),
87 (100%)
1.20 [d(J = 7), 6H], 1.45 [t (J = 7), 3H], 2.61 [m, 1H],
4.35 [q(J = 7), 2H], 7.86 [d(J = 2), 1H], 7.93 [d(J = 2), 1H] and
8.31 (sbr. 1H)
–
9a
0.97 [t(J = 7), 3H], 1.22 [d(J = 7), 6H], 1.45 (m, 2H), 1.77 (m, 2H),
2.61 (m, 1H), 4.27 [t(J = 7), 2H], 7.88 [d(J = 2), 1H], 7.93 [d(J = 2), 1H]
and 8.33 (sbr., 1H).
–
10a
11a
12a
13a
14b
17a
18a
19b
20a
1.40 [d(J = 7), 6H], 2.25 (sbr., 1H), 3.38 (m,1H), 3.96 [t(J = 5.4), 2H],
4.36 [t(J = 5.4), 2H], 8.09 [d(J = 2), 1H] and 8.31 [d(J = 2), 1H].
[M].+ (390,18%), 347 (100%), 331 (37.67%).
1.40 [d(J = 2.6), 6H], 3.27 (m, 1H), 3.85 [t(J = 2.6), 2H],
4.48 [t(J = 2.4), 2H], 8.10 [d(J = 1), 1H] and 8.31 [d(J = 1), 1H].
[M].+ (408,10%), 373 (100%), 331 (20%).
1.39 [d(J = 2.8), 6H], 3.72 (m, 1H), 4.85 (s, 2H), 8.10 [d(J = 2), 1H],
8.25 (s, 1H), 8.36 [d(J = 2), 1H].
–
1.36 [d(J = 2.8), 6H], 2.30 (s, 2H), 3.18 (m, 1H),
8.12 [d(J = 2), 1H], 8.38 [d(J = 2), 1H].
[M].+ (361,25%), 346 (35%), 333 (100%).
1.11 [d(J = 8.6), 6H], 1.91 (s, 3H), 2.65 [m, 1H], 7.67 [d(J = 2), 1H],
8.10 [d(J = 2), 1H] and at 9.50, 9.97 and 10.08 (3NH).
–
1.36 [d(J = 7.4), 6H], 3.45 [m, 1H], 3.90 (s, 3H), 7.01 [d(J = 8), 2H],
7.86 [d(J = 8), 2H], 8.10 [d(J = 2), 1H], 8.40 [d(J = 2)] and 8.74 (s, 1H).
[M].+ (479,3%), 346 (39.06 %), 331 (100%).
1.45 [d(J = 7), 6H], 3.05 [m, 1H], 8.15 [d(J = 2), 1H],
8.35 [d(J = 2), 1H] and 11.75 (sbr. 1H).
M.+ (346, 40%), 331 (100%), 316 (15%).
1.12 [d(J = 7), 6H], 2.65 [m, 1H], 7.98 [d(J = 2, 1H),
8.25 [d(J = 2), 1H] and 9.95 (s, 1H).
M.+ (421,13%), 350(52%), 320 (24%), 277(56%),
101 (13%), 71 (100%).
1.45 [d(J = 7), 6H], 3.05 [m, 1H], 8.16 [d(J = 1.2), 1H],
8.77 [d(J = 1.2), 1H] and 11.37 (sbr., 1H).
[M+2]+ (364,32%), 362(32%), 347(100%), 319(4.1%).
21a
22a
23a
–
[M].+ (376,56%), 361(100%).
1.8 (m, 9H), 3.8 [m, (1H, 2H) and 8.2 (dd, 2H)
–
–
1.46 [d(J = 7), 6H], 3.35 [m, 1H], 4.65 (s, 2H), ≈ at 7.38 (m, 5H) and
7.14 (dd, 2H).
24a
25
1.7 (m, 9H), 3.35 [m, 1H], 4.20 (s, 2H), 4.40 (q, 2H) and 8.20 (dd, 2H)
–
–
[M].+ (376,0.4%), 361 (11%), 345 (100%).
26a
0.98 [t(J = 7), 3H], 1.44 (m, 8H), 1.66 (m, 2H), 3.13 [m, 1H],
[M+2]+ (403,19%), [M].+ (401, 36%), 386(100%), 330(66%)
3.69 [q(J = 7), 2H], 5.62 (sbr., 1H), 7.76 (d(J = 2), 1H), 8.07 [d(J = 2), 1H].
27a
1.36 [d(J = 7), 6H], 3.17 [m, 1H], 4.88 (d, 2H), 5.87 (sbr., 1H),
7.37 (m, 5H), 7.76 [d(J = 2), 1H] and 8.09 [d(J = 2), 1H].
[M+2]+ (437,15.7%), [M].+ (45.7%), 329(2.4%),
106 (46.6%), 91(100%).
28a
29a
30b
31b
2.06 (s, 6H), 8.16 [d(J = 2), 1H], 8.76 [d(J = 2), 1H] and 11.01 (sbr., 1H).
2.17 (s, 6H), 8.3 [d(J = 2), 1H], 8.35 [d(J = 2), 1H]
–
[M].+ (399,11%), 364 (4.5%), 333 (100%).
[M].+ (380, 12%), 345 (100%), 316 (17.4%).
[M].+ (362, 39%), 344 (100%), 277 (69.6%).
2.02 (s, 6H), 8.18 [d(J = 2), 1H], 8.35 [d(J = 2), 1H] and 12.77 (sbr., 1H).
1.48 (s, 6H), 8.14 [d(J = 2), 1H], 8.21 [d(J = 2), 1H].
The signals of NH and OH are interacted with the solvent.
—————————————————————————————————————————————————————————————–
a = CDCl3, b = DMSO-d6
Arch. Pharm. Pharm. Med. Chem. 333, 365–372 (2000)

New Quinazoline and Benzoxazinone Derivatives
369
zoloquinazoline (32) (Scheme 2). The reaction probably
The structures of (14–19) were confirmed by correct ele-
mental analysis and spectroscopic data (Tables 6 and 7).
Furthermore, fusion of (2) with ammonium acetate (at
ca. 170 °C) gave the quinazolinone derivative (18)
(Scheme 1).
proceeds by replacement of chlorine atom at C by an
4
azido group which can be replaced as a good leaving
[17]
group
by a hydroxyl group during work-up of the
reaction.
The structure of (18) was confirmed, beside the microana-
lysis and spectral data, by the following chemical proofs:
Biological Activity
[16]
– Treatment of (18) with Lawesson’s reagent gave
the
Fungicides are still the most effective way to control plant
diseases. The search for new chemicals to control onion white
rot disease (caused by S. cepivorum) and onion neck rot
disease (caused by B. allii) is one of approaches to control
these serious diseases. Therefore, the effect of these new
benzoxazinone and quinazolinone derivatives were screened
at different concentrations.
corresponding 6,8-dibromo-2-isopropylquinazoline-4-
thione (20), which reacted with alkyl halides in the pres-
ence of base to give S-alkyl derivatives (21–24) rather than
N-alkyl derivatives. Only in the case of methyl iodide was
a mixture of S-alkyl (21) and N-alkyl derivatives (25) (2:1
ratio) formed (Scheme 2). The constitution of the mixture
1
has been detected from the H-NMR data which exhibit
signals for two isopropyl methyl groups at δ 1.41 (d) and
δ 1.42 (d), two isopropyl CH protons at δ 3.25 (m) and δ
Quinazolinone and benzoxazinone derivatives varied
greatly in their effect on mycelial growth and sclerotia for-
mation of S. cepivorum (Table 8). Derivatives 22 and 9 had
the greatest growth reduction effect on S. cepivorum, exhib-
iting 68–88% and 67–77% reduction of fungal growth, re-
spectively, but slightly decreasing the number of sclerotia at
20 ppm concentration. On the other hand, derivatives 17 and
31 were the most inhibitory to sclerotia formation, exhibiting
57–65% and 40–39% reduction in number of sclerotia, re-
spectively, and a moderate reduction on fungus growth. The
other examined samples exhibited lower effect on growth and
sclerotia formation.
3.32 (m), for S-CH at δ 2.72 (s), for N-CH at δ 3.66(s)
3
3
and for different four aromatic protons at δ 8.09 (d), δ 8.14
(d), δ 8.18 (d) and δ 8.33 (d), respectively.
Furthermore, desulphurization of (20) with primary amines
such as n-butylamine and benzylamine afforded the corre-
sponding 4-N-butyl or benzylamino quinazoline derivatives
(26 and 27), respectively (Scheme 2).
On the other hand, chlorination of the thione (20) with a
mixture of POCl /PCl afforded a mixture of 2-(2′-chloro-2′-
3
5
propyl)-6,8-dibromoquinazoline-4-thione (28) and 4-chloro-
2(2′-chloro-2′-propyl)-6,8-dibromoquinazoline (29)
(Scheme 2).
The derivatives generally reduced the growth of S.
cepivorum more when their concnetration was raised from 10
to 15 ppm, but a non-similar effect was detected when the
concentration increased to 20 ppm, which may be due to a
Chlorination of quinazolinone (18) with POCl /PCl in
3
5
a molar ratio of 1:1 yielded only the monochloro derivative
(30) (Scheme 2), while, when the reaction was carried out in
an excess of POCl /PCl , the dichloro derivative (29) was
stage of toxicity reverse phenomenon that appear in some
[18]
specific concentrations of fungicides
. This phenomenon
3
5
obtained as sole product (Scheme 2).
was detected before with dithiocarbamate and was attributed
The structures of (20–30) were confirmed by correct ele-
to inhibition of some biological constituents by fungicide as
1
[19]
mental analysis as well as IR, H-NMR, and MS (Tables 1
histidine, cystine, and thiolactic acid
.
and 2). The structure of both the monochloro derivative (30)
and the dichloro derivative (29) were further supported by the
following sequence of chemical proofs:
Quinazolinone and benzoxazinone derivatives also reduced
the growth of B. allii (Table 9). The fungus is greatly affected
by derivative 29 followed by derivative 31 exhibiting 50–0%
and 41–11% reduction of fungal growth respectively, at
20 ppm concentration. Other derivatives were less effective.
– Reaction of (30) with excess POCl /PCl mixture afforded
3
5
the dichloro derivative (29) (Scheme 2).
– Hydrolysis of (30) with boiling dilute Na CO solution
2
3
yielded the corresponding tertiary alcohol (31)
Experimental
(Scheme 2).
Melting points reported are uncorrected. IR spectra were recorded on
Pye-Unicam SP 1200 spectrophotometer using the KBr wafer technique. The
1H-NMR were determined on a Varian Gemini 200 MHz, Bruher AC-200
– Reaction of (29) with NaN in acetic acid gave the unex-
3
pected monochloroquinazolinone (30) instead of the tetra-
Arch. Pharm. Pharm. Med. Chem. 333, 365–372 (2000)

370
Shalaby and co-workers
Table 8. Effect of benzoxazinone and quinazolinone derivatives on mycelial growth and number of sclerotia of S. cepivorum.
—————————————————————————————————————————————————————————
Treatment
compound
Mycelial growth (cm) ppm
15 20 Means
Number of sclerotia
15 20
10
10
Means
—————————————————————————————————————————————————————————
22
4.5
2.7
5.4
6.2
8.0
8.1
7.3
8.8
7.5
9.0
9.0
6.9
2.8
3.8
4.8
5.6
7.5
6.3
6.9
8.4
7.3
8.8
9.0
6.4
2.8
2.9
4.6
5.0
5.2
5.7
7.8
7.5
7.5
8.3
9.0
6.0
3.3
3.1
4.9
5.6
6.9
6.7
7.3
8.2
7.4
8.7
9.0
57.4
87.5
26.3
46.8
62.0
76.4
75.5
76.9
84.4
28.6
97.3
65.3
82.8
85.3
26.0
38.3
74.1
57.8
47.4
74.9
76.6
26.0
97.3
62.0
107.5
92.8
85.8
66.0
11.0
73.3
60.5
32.3
49.4
16.1
97.3
62.9
82.5
62.2
46.0
50.3
49.0
69.1
61.1
61.3
70.1
23.5
97.3
7
31
29
9
20
19
23
28
17
Control
Means
—————————————————————————————————————————————————————————
L.S.D. 5% Treatment
L.S.D. 5% Concentration
L.S.D. 5% T. x Conc.
0.87
0.45
N.S.
7.83
N.S
13.56
3,5-Dibromo-2-isobutyroylamino-N-arylbenzamides (3–5)
Table 9. Effect of benzoxazinone and quinazolinone derivatives on mycelial
growth of B. allii.
——————————————————————————————
A mixture of (2) (0.01 mol) and primary amines, namely p-anisidine,
p-chloroaniline, and benzylamine (0.01 mol), in ethanol (30 mL) was re-
fluxed for 3 h. The solid separated after concentration of ethanol was filtered
and crystallized.
Treatment
compound
Mycelial growth (cm) ppm
15 20
10
Means
——————————————————————————————
29
31
20
9
28
19
22
23
7
17
Control
Means
5.2
6.1
6.9
7.5
6.8
6.8
7.8
8.0
8.4
8.5
9.0
7.2
5.2
6.0
5.8
6.8
7.1
7.3
7.0
7.4
7.8
7.6
9.0
6.8
4.5
5.3
6.0
5.8
7.1
7.1
6.8
6.8
7.1
7.2
9.0
6.2
4.9
5.8
6.2
6.7
7.0
7.0
7.2
7.4
7.7
7.7
9.0
N-[3,5-Dibromo-2-isobutyroylaminobenzoyl]piperidine and Morpholine
(6&7)
A mixture of (2) (0.01 mol) and secondary amines, namely piperidine and
morpholine (0.01 mol), in 1,4-dioxane (30 mL) was refluxed for 12 h. The
solid separated after concentration of the solvent was collected and crystal-
lized to give (6 & 7).
Ethyl 3,5-Dibromo-2-isobutyroylaminobenzoate (8)
A mixture of (2) (0.01 mol) and secondary amines, namely piperidine and
morpholine (0.01 mol), in ethanol (30 mL) was refluxed for 3 h. The solid
separated after concentration of ethanol was filtered and crystallized to give
the same product (8).
——————————————————————————————
L.S.D.5% Treatment
L.S.D.5% Concentration
L.S.D.5% T. x Conc.
0.43
0.22
0.74
Ethyl 3,5-Dibromo-2-isobutyroylaminobenzoate (8) and n-Butyl
3,5-Dibromo-2-isobutyroylaminobenzoate (9)
A mixture of (2) (0.01 mol) and ethyl alcohol or n-butyl alcohol (50 mL)
in pyridine (1 mL) was refluxed for 3 h, the solid formed after concentration
of the solvent was crystallized to give (8 & 9) respectively.
MHz using TMS as internal standard (chemical shifts in δ-scale). The mass
spectra were determined using HP model MS-5988 at electron energy 70 eV.
6,8-Dibromo-3-(2′-hydroxyethan-1′-yl)-2-isopropylquinazolin-4-one (10)
Synthesis of the Compounds
A mixture of (2) (0.01 mol) and ethanolamine (0.01 mol) was heated for
5 h. After cooling, the solid mass formed was treated with petroleum ether
60–80 °C to give (10).
3,5-Dibromo-N-isobutyroylanthranilic Acid (1)
To a solution of 3,5-dibromoanthranilic acid (0.01 mol) in anhydrous
pyridine (50 mL), isobutyryl chloride (0.02 mol) was added dropwise at
room temperature with stirring for 30 min; then the reaction mixture was
heated on a water bath for 5 h. After cooling, the reaction mixture was poured
on ice cold hydrochloric acid. The produced mass was filtered, washed with
water, and crystallized to give (1).
3-(2′-Chloroethan-1′-yl)-6,8-dibromo-2-isopropylquinazolin-4-one (11)
A mixture of (10) (1 g) and thionyl chloride (20 mL) was refluxed on a
water bath for 2 h. The solid formed after distillation of excess thionyl
chloride was crystallized to give (11).
6,8-Dibromo-2-isopropyl-(4H)-3,1-benzoxazin-4-one (2)
3,5-Dibromo-2-isobutyroylaminobenzoyl Hydrazine (12) and 3-Amino-6,8-
dibromo-2-isopropylquinazolin-4-one (13)
A mixture of (1) (0.01 mol) and acetic anhydride (50 mL) was heated on
a water bath for 5 h. The solid formed after removal of excess acetic
anhydride was triturated with petroleum ether 40–60 °C and crystallized to
give (2).
A mixture of (2) (0.01 mol) and hydrazine hydrate (0.01 mol) in ethanol
(30 mL) was stirred at room temperature for 30 min. The solid formed while
stirring was filtered and boiled with pet. ether 40–60 °C to give (13) and the
Arch. Pharm. Pharm. Med. Chem. 333, 365–372 (2000)

New Quinazoline and Benzoxazinone Derivatives
371
remaining solid was crystallized to give (12), which can be cyclized to (13)
by refluxing in n-butanol for 12 h. Also, compound (13) can be obtained by
fusion of (2) with hydrazine hydrate at 160–170 °C for 5 h.
4-N-(n-Butylamino)-6,8-dibromo-2-isopropylquinazoline (26) and 4-N-
(Benzylamino)-6,8-dibromo-2-isopropylquinazoline (27)
A mixture of (20) (0.01 mol) and n-butylamine or benzylamine (0.01 mol)
was heated at 160 °C for 1 h. The solid formed after cooling is treated with
toluene to give (26) or (27).
N-Acetyl-N′-(3,5-dibromo-2-isobutyroylamino)benzoyl Hydrazine (14) and
3-Acetylamino-6,8-dibromo-2-isopropylquinazolin-4-one (15)
2-(2′-Chloro-2′-propyl)-6,8-dibromquinazolin-4-thione (28) and 4-Chloro-
2-(2′-chloro-2′-propyl)-6,8-dibromoquinazoline (29)
A mixture of (12 or 13) (0.01 mol) and acetyl chloride (20 mL) was
refluxed on a water bath for 6 h. The solid formed while heating was
collected, washed with petroleum ether 40–60 °C and crystallized to give
(14) and (15) respectively. Compound (14) can be cyclized to (15) either by
heating above its melting point for 2 h. or by refluxing with phosphorus
oxychloride (10 mL) on water bath for 24 h.
A mixture of (20) (1 g), phosphorus oxychloride (20 mL) and phosphorus
pentachloride (l g) was heated on a water bath for 24 h. After cooling, the
reaction mixture was boiled with petroleum ether 80–100 °C to give (28),
the remaining residue was crystallized to give (29), which can be obtained
byheatingcompound(18) with a mixture of phosphorus oxychloride (20 mL)
and phosphorus pentachloride (1 g) on a water bath for 24 h. Refluxing
compound (29) and thiourea in ethanol for 5 h. gave (28) in 65% yield.
N-(3′,5′-Dibromo-2′-isobutyroylamino)benzoyl-4-methoxybenzaldehyde
Hydrazone (16) and 6,8-Dibromo-3-(4′-methoxybenzyliminio)-2-isopropyl-
quinazolin-4-one (17)
2-(2′-Chloro-2′-propyl)-6,8-dibromoquinazolin-4-one (30)
A mixture of (12 or 13) (0.01 mol) and p-anisaldehyde (0.01 mol) in
ethanol (50 mL) was refluxed for 6 h. The solid formed while heating was
collected and crystallized to give (16) and (17) respectively. Compound (16)
can be cyclized to (17) either by heating with phosphorus oxychloride
(l0 mL) on water bath for 24 h or by fusion at 280 °C for 2 h.
A mixture of (18) (0.01 mol), phosphorus oxychloride (0.0l mol), and
phosphorus pentachloride (0.01 mol) was heated on a water bath without
solvent or refluxed in dry toluene for 24 h. After cooling, the reaction mixture
was treated with petroleum ether 80–l00 °C or the solvent (dry toluene) was
concentrated and treating the solid mass formed with petroleum ether 80–
100 °C to give (30).
6,8-Dibromo-2- isopropylquinazolin-4-one (18)
Procedure (A)
2-(2′-Chloro-2′-propyl)-6,8-dibromoquinazolin-4-one (30)
A mixture of (29) (0.01 mol) and sodium azide (0.01 mol) in glacial acetic
acid (30 mL) was refluxed for 8 h. After cooling the reaction mixture is
poured in ice cold water, the solidformedisfiltered, washedwithwater, dried
and crystallized from petroleum ether 80–l00 °C to give (30) in 80% yield
which was identified by comparison of mp, m.mp, TLC, and spectral data
with those of a sample prepared by the previous method
A mixture of (2) (0.01 mol) and ammonium acetate (0.04 mol) was fused
at 160 °C for 6 h. After cooling the solid mass formed was triturated with
warm water, filtered, washed with water, and crystallized to give (18) in 90%
yield.
Procedure (B)
Conversion of (30) to (29)
To a solution of (12 or 13) (1 g) in concentrated hydrochloric acid (30 mL)
at 0 °C, cold sodium nitrite solution (1 g/10 mL of water) was added drop-
wise within 15 min, with stirring. The reaction mixture was stirred at 0 °C
for 3 h. The solid produced was filtered, washed with water, and crystallized
to give (18) in 80% yield which was identified by comparison of mp, m.mp,
TLC, and spectral data with those of a sample prepared by the previous
method.
A mixture of (30) (1 g) , phosphorus oxychloride (20 mL), and phosphorus
pentachloride (1 g) was heated on a water bath for 24 h. After cooling the
reaction mixture was boiled with toluene to give (29) in 65% yield which
was identified by comparison of mp, m.mp, TLC, and spectral data with those
of a sample prepared by the previous method.
6,8-Dibromo-2-(2′-hydroxy-2-propyl)quinazolin-4-one (31)
5-(3′,5′-Dibromo-2′-N-isobutyroylamino)phenyl-1,3,4-oxadiazole-2-thione
(19)
A mixture of (30) (1 g), sodium carbonate (30 mL,10%) was, refluxed for
5 h. The solid formed after neutralization with nitric acid is filtered. washed
with water, dried, and crystallized to give (31).
To a solution of (12) (0.01 mol) in ethanol (50 mL) containing KOH (1 g),
carbon disulphide (20 mL) was added dropwise at room temperature within
30 min. The reaction mixture was refluxed on a water bath for 10 h. The
solvent was removed and the residue was diluted with cold water and
neutralized with concentrated hydrochloric acid. The solid separated was
filtered washed with water and crystallized to give (19).
Experimental Determination of Biological Activity
Quinazolinone and benzoxazinone derivatives listed in Tables 8 and 9
were added to PDA medium at concentrations 10, 15, 20 ppm and hand
shaken before plating. Plates were incubated with 0.5 cm diameter discs of
10 days-old PDA culture of S. cepivorum. Plates were incubated at 20 °C till
the fungus growth filled up the whole space of the control plates, then
diameters of mycelial growth were recorded in the other plates.
Numbers of sclerotia were microscopically counted on 0.5 cm diameter
discs of treatment cultures after three weeks incubation. The same technique
was applied to determine sensitivity of B. allii growth for the above-men-
tioned treatments.
6,8-Dibromo-2-isopropylquinazolin-4-thione (20)
A mixture of (18) (0.01 mol) and Lawesson’s reagent (0.005 mol) in dry
toluene (50 mL) was refluxed for 6 h. The solid formed after concentration
of the solvent was collected and crystallized to give (20).
The experiments were designed complete randomized with factorial ar-
rangement. Data were statistically analyzed by F-test, and LSD used to verify
between treatments.
6,8-Dibromo-4-S-alkylthia-2-isopropylquinazolines (21–24) and
6,8-Dibromo-3-N-methyl-2-isopropylquinazolin-4-thione (25)
To a solution of (20) (0.01 mol) in dry acetone (30 mL) in presence of
sodium carbonate (1 g), methyl iodide, ethyl bromide, benzyl chloride, or
ethyl bromoacetate (0.01 mol) was added, then the reaction mixture was
refluxed on a water bath for 12 h. The solid formed after evaporation of the
solvent was collected, washed with warm water, dried and crystallized from
petroleum ether 40–60 °C to give unseparated mixture of (21) and (25) as
colourless crystals in 55% yield (in case of methyl iodide) and (22–24).
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Received: March 31, 2000 [FP474]
Arch. Pharm. Pharm. Med. Chem. 333, 365–372 (2000)