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A Novel Series of Biologically Active

Quinazolinones through Ring Transformation of

2-(5-Nitrofuran-2-yl)-4H-benzo[d][1,3]oxazin-4- one

Maher A. El-Hashasha, Mohammad E. Azaba and Jehan M.Morsyb

Abstract: 2-(5-nitrofuran-2-yl)-4H-benzo[d][1,3]oxazin-4-one(2 ) was subjected to reaction with NH 2 NH 2 .H 2 O, formamide, NH 2 OH.HCl to give the quinazolinones 3-5, respectively. W hen benzoxazinone 2 was subjected to the reaction with1, 2-phenylene diamine or thiosemicarbazide under different conditions ,it produced the quinazolinone derivatives 6-9, respectively. Reaction of the aminoquinazolinone 3 with acetyl chloride, benzoyl chloride, benzenesulphonyl chloride , ethyl chloroacetate or ethyl anthranilate, furnished the quinazolinone derivatives 10a,b-13, respectively. On the other hand, reaction of 3 with CS 2 / NaOH gave the salt 14, which upon treatment with dimethyl sulphate furnished the thioester 15, which underwent reactions with primary and secondry amines to give the thioamides 16a-c. Finally, the hydroxyquinazolinone 4 was treated with Ac 2 O or ethyl chloroacetate to afford the acetoxy compound 17 and the ester 18, respectively.The later reacted with NH 2 NH2 .H2 O to produce the hydrazide19.

Keywords: Quinazolinone, methyldithioate, benzimidazoloquinazoline, triazolo[1,5-c]quinazoline, hydrazinecarbothioamide.

Introduction: quinazolinones belong to the most frequently reported heterocyclic compounds in

albicans).The structures of the new synthesized compounds were confirmed by IR, 1H-NMR, mass

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medicinal chemistry, which possess diverse biological
activities like antineoplastic [1]-[3], anti- inflammatory, analgesic [4]-[8], antihistaminic [9], anti-hypertensive [10], cardiac stimulant activity [11], antimalarial [12], anticonvulsant [13]-[15], antimicrobial [16]-[18], etc.Based on the aforementioned facts and as a continuation of our previous efforts [19]-[24] aiming to establish heterocyclic compounds with antimicrobial activity, we prepared 2-(5-nitrofuran-2-yl)-4H- benzo[d][1,3]oxazin-4-one(2),which underwent different reaction to producebiologically active quinazolinone derivativesthrough hetercyclic ring transformation.The synthesized compounds were screened for their activity against Gram negative Escherichiacoli, Gram positive bacteria (Staphylococcus aureus, Bacillus subtilis) and pathogenic fungi (Saccharomyces cerevisiae, Candida

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a Department of chemistry, Faculty of Science, Ain Shams
University, Abbasiya 11566, Cairo, Egypt.
b Laboratory of Synthetic Organic Chemistry, Chemistry
Department, Faculty of Education, Roxy 11711, Cairo,
Egypt.
Corresponding author: morsy_jehan@yahoo.com

Refluxing benzoxazinone 2 with NHR2RNHR2R.HR2RO in dioxane afforded the N-aminoquinazolinone 3, while

spectra and elemental analyses.

Results and Discusion:

The key starting material, 2-(5-nitrofuran-2-yl)-4H- benzo[d][1,3]oxazin-4-one(2), was synthesized (Scheme
1) from 5-nitrofuroyl chloride and anthranilic acid in the presence of dry pyridine via N-acylantharanilic acid derivative 1, which underwent ring closure upon heating with AcR2RO to afford the title compound 2 [25].
heating 2 in excess of formamide produced the quinazolinone derivative 4 [26]. When 2 was heated with

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hydroxylamine hydrochloride in pyridine, hydroxylquinazolinone derivative 5 [27] was obtained
(Scheme 2).

O

OH O2N O

+

O O

OH Cl dry pyridine

NH2

NH

O 1

Ac2O

-H2O

O NO2

O

Scheme 1

O

O NO2

N

2

NH2NH2.H2O Dioxane

O

O


O

NH2

N

O N

3


O

H

NO2

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O NO2

N

2

excess HCONH2

NH2OH.HCl pyridine

Scheme 2

N

O NO2

N

4


O

OH N

O NO2

N

5

With the aim of expanding the synthetic potential of benzoxazinone 2 , we have studied its reaction with o-phenylenediamine and thiosemicarbazide under different conditions. Thus, refluxing 2 with 1,2-phenylenediamine in AcOH in the presence of fused NaOAc furnished the corresponding aninophenylquinazolinone 6, while the benzimidazoloquinazoline derivative 7 was obtained when the same reaction was performed under fusion conditions.
Similarly, reaction of thiosemicarbazide with
benzoxazinone 2 in pyridine produces the thiourea derivative 8, but when the reaction was carried out in AcOH, the triazoloquinazoline derivative 9 was obtained
(Scheme 3).
According to our speculation, these results can
be interpreted as follows: The N-nucleophiles attack the
benzoxazinone 2 in a fashion in which the amino group
first undergoes H-bonding to the N-atom of the
heterocycle. Then, the amino group reacts by
nucleophilic addition at the azavinylic C(2) to form an inner amidinium salt, which subsequently is dehydrated to the quinazolinone derivative (Scheme 4).In case of compounds 7 and 9, after the quinazolinone derivative was formed , a heterocyclic ring closure took place through a condensation reaction between NH2 and C=O groups.

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H2N

O

H2N

NH2

CH3COONa

AcOH

N

O NO2

N

6

O

O

O NO2

N

2

CH3COONa f usion

N

N

O NO2

N

7

O

NH2

S

NHNH2

pyridine

N

O NO2

N

8

S N

Scheme 3

O

AcOH AcONa


O

N

O NO2

N

9


O

R

O


+ H2N R



O H -H2O N N R

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N Ar N H

N Ar

Ar =

O NO2

Ar

Scheme 4

R = NH , H, OHH2N

, -NH-CS-NH2

Compound 3 is considered as key starting material for a diversity of heterocyclic compounds; because it has hydrogen atoms of amino group which can be easily changed. In this context compound 3 was converted to the corresponding amides 10a, b and 11 on treatment with acetyl chloride, benzoyl chloride or benzene sulphonyl chloride in pyridine. Furthermore, N- aminoquinazolinone 3 was converted to more interesting diamide derivative 12 via reaction with ethyl chloroacetate in boiling dioxane. The reaction takes place via nucleophilic displacement at acyl moiety and not at the alkyl halide moiety. This seems to be logic because the energy barrier required for the tetrahedral mechanism is less than SN2 mechanism and
consequently the reaction proceeds through the first mechanism rather than the second one. The energy barrier that hampers SN2 can be understood from the fact that in case of tetrahedral mechanism, the system receives much of its "energy payment" from the formation of the new bond ( N-CO ) before having to pay its" energy dept" for the breaking of ( C-OR ) bond.
On the other hand, refluxing 3 with ethyl anthranilate under the same conditions furnished only the mono amide derivative 13 (Scheme 5). The formation of mono amide rather than the di-amide may be attributed to the steric hinderance caused by the first aniline moiety.

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RCOCl pyridine



O O

NH R N

O NO2

N

10




R = Me, Ph

O

SO2


O

NH2

N

O NO2

N

3

PhSO2Cl pyridine

Cl CO2Et

Dioxane

NH N

O NO2

N

11




O COCH2Cl

N

N COCH2Cl

O NO2

N

12


O NH2

CO2Et

NH2

Dioxane

O

NH N

O NO2

N

13

Scheme 5

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The point of interest in this investigation is
study of the behavior of the aninoquinazolinone 3
towards CS2 . Thus, when quinazolinone 3 in DMSO was added to CS2 and NaOH, it afforded the sodium salt of
carbamodithioate 14 which reacted with Me2 SO4 to give
dithioate ester 15 which upon treatment with
NH2 NH2 .H2 O and secondary amines (namely, piperidine or morpholine) in DMF yielded thioamide
derivatives 16a-c were produced (Scheme 6).





O

NH2

N

O N

3

NO2

CS2/NaOH DMSO

O S

NH S Na

N

O NO2

N

14



O S

NH R N

O NO2

N

16

1ory and/or 2ory amines

(CH3)2SO4



O S NH

N

O N

15

SCH3

NO2

R, a = -NH-NH2


b = N


c = N O

Scheme 6

Finally, the structure of the 3- hydroxyquinazolinone derivative 5 was inferred chemically by studying its behavior towards C- electrophiles. In the presemt work, treatment of 5 with boiling Ac2 O afforded 3-acetyloxyquinazolinone derivative 17. On the other hand, the conversion of 5 into
ethyl acetate derivative 18 was achieved via the interaction with ethyl chloroacetate in the presence of anhydrous K2 CO3 in boiling dry acetone. Compound 18 was chemically confirmed by the reaction with hydrazine hydrate in boiling ethanol to afford the acetohydrazide derivative 19 (Scheme 7).

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O

OH N

O NO2

N

5

Ac2O



O O

O N

O NO2

N

17


Cl CO2Et anhyd.K2CO3



O O

O

N O

O NO2

N

18

NH2NH2.H2O EtOH

Scheme 7



O O

O

N NHNH2

O NO2

N

19

Biological activities. Antibacterial Activity

All of the new synthesized compounds were screened for in vitro antibacterial activity against gram negative bacteria Serratiamarcesens, and proteusmerabitis and

Antifungal Activity

Most of the new synthesized compounds were
screened for in vitro antifungal activity against
Aspergillus ochraceus Wilhelm and penicillium

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gram positive bacteria, Staphylococcus, Aureus and
Bacillus cereus. The standard drug used was Ampicilin.
The investigation of antibacterial screening reported in table 1 revealed that some of the newly synthesized compounds showed moderate to good inhibition at 100
µg/ml in DMF.Compounds 3,4,8,9,18 and 19 exhibited high activity.
chrysogenumthom by agar diffusion technique. The standard drug used was Mycostatine. The investigation of antifungal screening reported in table1 revealed that some of the newly synthesized compounds showed moderate to good inhibition at 100 µg/ml in DMF. Compounds 3,4,7,8,15,16,17,18 and 19 showed good activity.
Table 1 : Antimicrobial activity of the synthesized compounds.

Compd

No

Antibacterial Activity

Antifungal Activity

Compd

No

Gram positive

Gram negative

Aspergillus

Penicillium

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++
++
+++
+++
++++
++
++
+++
+++
++++
++
++
+++
+++
++++
++
++
+++
+++
++++
++
++
++
++
++++
The width of the zone of inhibition indicates the potency of antibacterial activity; (-) no antibacterial activity; (+) less activity with the diameter of the zones equal to 0.2 – 0.5 cm, (++) moderate activity with the diameter of the zones equal to 0.6-1.4 cm; (+++) marked high activity with the diameter of the zones equal to 1.5 – 3.0 cm; (++++) very high activity with the diameter of the zones (over 3.0 cm).

Experimental:

All melting points are uncorrected and were determined
on Gallen Kamp electric melting point apparatus. The
microanalyses were within the acceptable limits (±0.4%) of the theoretical values and were carried out in theMicroanalytical Center, Cairo University, Egypt. IR spectra (in KBr, cm-1/ν) on Shimadzu FTIR 8101 PC.1H- NMR spectra were recorded on a Varian 300 MHz with residual proton signal of the deuterated solvent as the internal reference ( H = 7.26 ppm for CDCl3 and  H =
2.51 ppm for DMSO-d6 ). The chemical shifts were
reported as parts per million (δ ppm) and coupling constant (J)values are given in Hz using tetramethylsilane (TMS) as internal standard from downfield to upfield.The mass spectra were recorded on Shimadzu GCMS-QP-1000EX mass spectrometer at 70 e.v. Homogeneity of the synthesized compounds was checked by Merk Thin-layer chromatography (TLC) aluminium sheet silica gel 60 F254 with detection by UV quenching at 254 nm.Reagents and solvents were used as obtained from the supplier without further purification.

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2-(5-nitrofuran-2-yl)-4H-benzo[d][1,3]oxazin-4-one (2). To a solution of anthranilic acid (1.37 g, 0.01 mol) in pyridine (30 ml) 5-nitrofuran-2-carbonyl chloride (3.51 g,

0.02 mol) was added during 0.5 hr. Then, the reaction
mixture was stirred for additional 1 hr at room
temperature. The reaction mixture was poured on
ice/HCl and left overnight. The precipitate obtained was
filtered off, washed by water (3x 100) and dried to give the anthranil1. A suspension of 2-(5-nitrofuran-2- carboxamido)benzoic acid (1) (2.76g, 0.01 mol) in freshly distilled acetic anhydride (40 ml) was heated under reflux for 4 h and then concentrated under vacuum. The residue was crystallized from benzene to afford compound 2.
Compound 2: Yield: 81% (2.1g), m.p.152-154oC, IR :1619 (C=N), 1752 (C=O of -lactone). 1H-NMR (CDCl3 ): 6.78-
8.33 (m, 6H, Ar-H, and furan-H). MS: 258 (M.+). Anal.calc. for C12 H6 N2 O5 (258): C: 55.81, H:2.33, N:10.85; found: C: 56.09, H:2.53, N:11.08.

3-Amino-2-(5-nitrofuran-2-yl)quinazolin-4(3H)-one (3). A mixture of benzoxazinone 2 (2.58, 0.01 mol) and hydrazine hydrate (1.0 g, 0.02 mol) was heated under reflux in dioxin (30 ml) for 3 hr. After concentration, the

Compound 5: Yield 69% (1.89g), m.p.231-233oC, IR :1623 (C=N), 1671 (C=O), 3374 (OH). 1H-NMR (CDCl3 ): 6.84-
8.42 (m, 6H, Ar-H, and furan-H), 10.83 (br., H, OH, D2 O
exchangeable). MS : 273 (M.+). Anal. calc. for C12 H7 N3 O5
(273): C: 52.75, H: 2.56, N: 15.38; found: C: 53.00, H: 2.44,
N: 15.67.

3-(2-aminophenyl)-2-(5-nitrofuran-2-yl)quinazolin-

4(3H)-one (6).

A solution of compound 2 (2.58g, 0.01 mol) and o-
phenylenediamine (1.08g, 0.01 mol) in acetic acid (30 ml), in presence of fused sodium acetate (0.6g), was heated under reflux for 2hr. The reaction mixture was left to cool and then poured into water (100 ml) with continuous stirring. The solid the separated out was filtered off and crystallized from benzene producing compound6. Compound 6: Yield 72% (2.51g), m.p.256-258oC, IR :1615 (C=N), 1665 (C=O), 3187, 3339 (NH2 ). 1H-NMR (CDCl3 ):
6.77- 8.35 (m, 10H, Ar-H, and furan-H), 9.11 (br., 2H, NH2 , D2 O exchangeable). MS: 348 (M.+). Anal. calc. for C18 H12 N4 O4 (348): C: 62.07, H: 3.45, N: 16.09; found: C:
61.77, H: 3.68, N: 15.78.

2-(5-nitrofuran-2-yl)benzimidazolo[1,2-c]quinazoline

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solid that separated out, was filtered off, dried and then
recrystallized from dioxan to produce the
aminoquinazolinone 3.
Compound 3: Yield 77% (2.1g), m.p.222-224oC, IR :1608 (C=N), 1663 (C=O), 3224, 3317 (NH2 ). 1H-NMR (DMSO- d6 ): 6.89- 8.39 (m, 6H, Ar-H, and furan-H), 9.25 (br., 2H, NH2 , D2 O exchangeable). MS: 272 (M.+). Anal.calc. for
C12 H8 N4 O4 (272): C: 52.94, H: 2.94, N: 20.59; found: C:
53.18, H: 3.19, N: 20.38.

2-(5-nitrofuran-2-yl)quinazolin-4(3H)-one (4).

A solution of benzoxazinone2 (2.58 g, 0.01 mol) in formamide (15 ml) was refluxed for 2 hr. The reaction mixture was left to cool and was then poured onto ice/H2O. The solid deposited was separated by filtered, dried and recrystallized from ethanol to give the quinazoline4.
Compound 4: Yield 75% (1.93g), m.p.245-247oC, IR: 1612 (C=N), 1668 (C=O), 3194 (NH). 1H-NMR (CDCl3 ): 6.81-
8.31 (m, 6H, Ar-H, and furan-H), 11.1 (br., H, NH, D2 O
exchangeable). MS: 257 (M.+). Anal. calc. for C12 H7 N3 O4 (257): C: 56.03, H: 2.72, N: 16.34; found: C: 55.87, H: 3.00, N: 16.66.

3-Hydroxy-2-(5-nitrofuran-2-yl)quinazolin-4(3H)-one

(5).

A mixture of benzoxazinone 2 (2.58 g, 0.01 mol) and hydroxylamine hydrochloride (2.09 g, 0.03 mol) in pyridine (30 ml) was heated under reflux for 3hr. After cooling, the reaction mixture was poured into ice/HCl. The solid that obtained was filtered off and crystallized from ethanol affording the hydroxyl quinazolinone derivative 5.

(7).

A mixture of benzoxazinone 2 (2.58g, 0.01 mol) and o- phenylenediamine (1.08g, 0.01 mol) and fused sodium acetate (0.6g), was heated in an oil bath at 170oC for 2 hr. The reaction mixture was left to cool and then poured into hot water (100 ml) with continuous stirring. The solid the separated out was filtered off and crystallized from dioxne to give compound 7.
Compound 7: Yield 60% (1.98g), m.p.287-289oC, IR : 1620 (C=N). 1H-NMR (DMSO-d6 ): 6.72- 8.40 (m, 10H, Ar-H, and furan-H). MS: 330 (M.+). Anal. calc. for C18 H10 N4 O3 (330) : C: 65.45, H: 3.03, N: 16.97; found: C: 65.76, H: 2.88,
N: 17.22.

1-(2-(5-nitrofuran-2-yl)-4-oxoquinazolin-3(4H)- yl)thiourea (8).

Thiosemicarbazide (0.91 g, 0.01 mol) was added to a solution of benzoxazinone2 (2.58 g, 0.01 mol) in pyridine (20 ml) and refluxed for 4 hr. After cooling the reaction mixture was poured into ice/HCl. The solid that was separated out filtered off, dried and then crystallized from ethanol to produce8.
Compound 8: Yield 71% (2.35g), m.p.266-269oC, IR
:1630(C=N), 1679 (C=O), 3198, 3275 and 3371 (NH, NH2 ).

1H-NMR (DMSO-d6 ): 6.81- 8.37 (m, 6H, Ar-H, and furan- H) 9.44 (br., 2H, NH2 , D2 O exchangeable), 10.74 (br., H, NH, D2 O exchangeable). MS: 331 (M.+). Anal. calc. for C13 H9 N5 O4 S (331): C: 47.13, H: 2.72, N: 21.15, S: 9.67; found: C: 46.87, H: 2.55, N: 20.88, S: 9.36.

5-(5-nitrofuran-2-yl)-[1,2,4]triazolo[1,5-c]quinazoline-

2(3H)-thione (9).

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To a solution of compound 2(2.58 g, 0.01 mol) in glacial acetic acid (30 ml), thiosemicarbazide (0.91 g, 0.01 mol) was added, in the presence of sodium acetate , and heated under reflux for 4 h. The mixture was allowed to stand overnight, and the separated solid was crystallized from ethanol to afford the triazolo derivative 9. Compound 9: Yield 71% (2.35g), m.p.237-239oC, IR :1153 (C=S), 1610(C=N), 3275(NH). 1H-NMR (DMSO-d6 ): 6.70-
8.21 (m, 6H, Ar-H, and furan-H) 10.54 (br., H, NH, D2 O
exchangeable). MS: 313 (M+). Anal. calc. for C13 H7 N5 O3 S (313): C: 49.84, H: 2.24, N: 22.36, S: 10.22; found: C: 50.16,
H: 2.66, N: 22.63, S: 9.88.

N-(2-(5-nitrofuran-2-yl)-4-oxoquinazolin-3(4H)- yl)acetamide (10a) and N-(2-(5-nitrofuran-2-yl)-4- oxoquinazolin-3(4H)-yl)benzamide (10b)

A mixture of quinazolinone 3 (2.72 g,0.01 mol) and acetyl
chloride and/or benzoyl chloride (0.79 g, 1.77 g, 0.01
mol) in pyridine (20 ml) was refluxed for 3 hr. The cold mixture was poured into ice/HCl. The separated solid was filtered off, dried and crystallized from toluene to give 10a and benzene to afford 10b, respectively. Compound 10a: Yield 81% (2.55g), m.p.201-203oC, IR
:1618(C=N), 1651,1686(C=O),3289(NH). 1H-NMR
acetamide derivative 12.
Compound 12: Yield 45% (1.91 g), m.p.256-258oC, IR :
761 (C-Cl), 1616 (C=N) , 1655, 1674 (C=O). 1H-NMR (CDCl3): 4.39 (s, 4H, 2CH2 Cl), 6.78- 8.25 (m, 6H, Ar-H, and furan-H). MS: 424 (M.+). Anal. calc. for
C16 H10 Cl2 N4 O 6 (424): C: 45.28, H: 2.36, N: 13.21, Cl: 16.51;
found: C: 45.00, H: 2.65, N: 12.93, Cl: 16.36.

2-Amino-N-(2-(5-nitrofuran-2-yl)-4-oxoquinazolin-

3(4H)-yl)benzamide (13)

A solution of the quinazolinone 3 (2.72 g, 0.01 mol) and aminoethylbenzoate (1.65 g, 0.01 mol) in dioxan (30 ml) was heated under reflux for 3 hr. The reaction mixture was concentrated and left to cool. The residue obtained was filtered off, dried and recrytallized from toluene to give compound 13.
Compound 13: Yield 59% (2.31 g), m.p.193-195oC, IR:
1611(C=N), 1668(C=O), 3188, 3282 and 3379 (NH, NH2).

1H-NMR (CDCl3 ): 6.86- 8.28 (m, 10H, Ar-H, and furan- H), 9.41 (br., 2H, NH2 , D2 O exchangeable), 10.66 (br., H, NH, D2 O exchangeable). MS: 391 (M.+). Anal. calc. for

C19 H13 N5 O5 (391): C: 58.31, H: 3.32, N: 17.90; found: C:
58.60, H: 3.66, N: 19.23.

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(CDCl3 ): 2.29 (s, 3H, COCH3 ), 6.88- 8.39 (m, 6H, Ar-H,
and furan-H) 10.61 (br., H, NH, D2 O exchangeable). MS:
314 (M+). Anal. calc. for C14H10N4O5 (314): C: 53.50, H:
3.18, N: 17.83; found: C: 53.77, H: 3.47, N: 18.14.
Compound 10b: Yield 71% (2.67g), m.p.189-191oC, IR
:1621(C=N), 1656,1690(C=O),3278(NH). 1H-NMR (CDCl3 ): 6.79- 8.36 (m, 11H, Ar-H, and furan-H) 10.89 (br., H, NH, D2 O exchangeable). MS: 376 (M.+). Anal. calc. for C19 H12 N4 O5 (376): C: 60.64, H: 3.19, N: 14.89; found: C: 60.30, H: 3.50, N: 15.16.

N-(2-(5-nitrofuran-2-yl)-4-oxoquinazolin-3(4H)- yl)benzensulphonamide (11)

To a solution of the quinazolinone 3 (2.72 g, 0.01 mol) in
pyridine (20 ml), benzene sulphonyl chloride (1.76 g, 0.01
mol) was added. The reaction mixture was allowed to heat under refluxed for 3 hr. After cooling, the mixture was poured into ice/HCl. The separated solid was filtered off, dried and crystallized from toluene affording the sulphonamide derivative 11.
Compound 11: Yield 76% (3.13g), m.p.228-230oC, IR
:1612(C=N), 1685(C=O),3249(NH). 1H-NMR (CDCl3 ):
6.81- 8.29 (m, 11H, Ar-H, and furan-H) 10.62 (br., H, NH, D2 O exchangeable). MS: 412 (M.+). Anal. calc. for C18 H12 N4 O6 S (412): C: 52.43, H: 2.91, N: 13.59, S: 7.77;
found: C: 52.11, H: 3.23, N: 13.91, S: 8.06.

2-Chloro-N-(2-chloroacetyl)-N-(2-(5-nitrofuran-2-yl)-4- oxoquinazolin-3(4H)-yl)acetamide (12).

A mixture of quinazolinone 3 (2.72 g, 0.01 mol) and ethyl
chloroacetate (1.23 g, 0.01 mol) in dioxan was refluxed for 4 hr. The solid that was separated after cooling, filtered off and crystallized from ethanolproducing the

Methyl 2-(5-nitrofuran-2-yl)-4-oxoquinazolin-3(4H)-

ylcarbamodithioate (15).

To a vigorously stirred solution of quinazolinone 3 (5.44 g, 0.02 mol) in DMSO (10 ml) at room temperature, carbon disulphide (1.6 ml, 0.026 mol) and sodium hydroxide (1.2 ml, 0.02 mol) were added dropwise during 30 min, stirring was continued for further 30 min, the sodium salt 14 was precipitated. Dimethylsulphate (2.5 g, 0.02 mol) was then added to the reaction mixture at 5-10°C and stirring was continued for additional 3 h. The reaction mixture was filtered off, washed with H2O (3x100 ml), dried and crystallized from toluene affordingthe methyl dithioate derivative 15.
Compound 15: Yield 69% (5.00 g), m.p.179-182o C, IR
:1323 (C=S), 1624(C=N), 1673(C=O), 2901 (C-H aliph),
3223(NH). 1H-NMR (CDCl3 ): 2.38 (s, 3H, S-CH3 ), 6.69-
8.22 (m, 6H, Ar-H, and furan-H), 9.19 (br., H, NH, D2 O
exchangeable). MS: 362 (M.+). (M+). Anal. calc. for
C14 H10 N4 O4 S2 (362): C: 46.41, H: 2.76, N: 15.47, S: 17.68;
found: C: 46.10, H: 3.03, N: 15.21, S:18.02.

N-(2-(5-nitrofuran-2-yl)-4-oxoquinazolin-3(4H)- yl)hydrazinecarbothioamide (16a), N-(2-(5-nitrofuran-2- yl)-4-oxoquinazolin-3(4H)-yl)piperidine-1- carbothioamide (16b) and N-(2-(5-nitrofuran-2-yl)-4- oxoquinazolin-3(4H)-yl)morpholine-4-carbothioamide (16c).

A mixture of the methyl dithioate ester derivative 15
(3.62 g, 0.01 mol) and hydrazine hydrate, piperidine and/or morpholine (1.0 g, 1.7 g, 1.74 g, 0.02 mol respectively) in DMF (20 ml) was refluxed for 22 h, then cooled and poured into ice/H2O, the residue obtained was filtered off, dried and crystallized from dioxan,

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ISSN 2229-5518

benzene, respectively to give 16a-c.
Compound 16a: Yield 79% (2.73 g), m.p.247-249oC, IR
:1328 (C=S), 1618(C=N), 1669(C=O), 3182, 3263, 3311(NH,
NH2). 1H-NMR (DMSO-d6): 6.73- 8.33 (m, 6H, Ar-H, and furan-H), 9.09 (br., 2H, NH2 , D2 O exchangeable), 9.38
(br., H, NH, D2 O exchangeable), 10.78 (br., H, NH, D2 O exchangeable). MS: 346 (M.+). Anal. calc. for C13 H10 N6 O4 S (346): C: 45.09, H: 2.89, N: 24.28, S: 9.25; found: C: 44.80, H: 3.18, N: 24.01, S: 8.94.
Compound 16b: Yield 70% (2.79 g), m.p.208-210oC, IR
:1324 (C=S), 1613(C=N), 1678(C=O), 3244(NH). 1H-NMR (CDCl3 ): 1.34 (m, 6H piperidine ring), 2.91 (t, J = 7.2, 4H, CH2 -N-CH2 ), 6.77- 8.40 (m, 6H, Ar-H, and furan-H),
10.53 (br., H, NH, D2 O exchangeable). MS: 399 (M.+). (M+). Anal. calc. for C18 H17 N5 O4 S (399): C: 54.14, H: 4.26,
N: 17.54, S: 8.02; found: C: 54.39, H: 4.57, N: 17.88, 8.33.
Compound 16c: Yield 69% (2.76 g), m.p.231-233oC, IR :
1321 (C=S), 1622(C=N), 1676(C=O), 3252(NH). 1H-NMR (CDCl3 ): 2.93 (t, J = 7.2, 4H, CH2 -N-CH2 ), 3.22 (t, J = 7.4,
4H, CH2 -O-CH2 ), 6.71- 8.31 (m, 6H, Ar-H, and furan-H),
10.39 (br., H, NH, D2 O exchangeable). MS: 401 (M.+). Anal. calc. for C17 H15 N5 O5 S (401): C: 50.87, H: 3.74, N:
17.46, S: 7.98; found: C: 51.18, H: 4.03, N: 17.77, 8.31.

Ethyl 2-(2-(5-nitrofuran-2-yl)-4-oxoquinazolin-3(4H)- yloxy)acetate (18).

A mixture of compound 5 (2.73 g, 0.1 mol), ethyl
chloroacetate (2.72g, 0.02 mol) and anhydrous potassium
carbonate (0.04 mol) in dry acetone (60 ml) was reflxed for 22 h on water bath. The excess solvent was removed by rotator evaporator, and the residue was poured on to cold water. The obtained solid was filtered off and crystallized from toluene affording the ethyl acetate derivative 18.
Compound 18: Yield 84% (3.02 g), m.p.208-210oC, IR
:1613(C=N), 1670, 1722(C=O), 3254 (NH). 1H-NMR (CDClR3R):1.35 (t, J = 6.7, 3H, COCH2CH3), 3.89 (q, J = 7.3,

2H, COCHR2RCHR3R), 4.58 (s, 2H, OCHR2RCO), 6.80- 8.36 (m,

6H, Ar-H, and furan-H). MS: 359 (M.+). Anal. calc. for

CR16RHR13RNR3ROR7R (359): C: 53.48, H: 3.62, N: 11.70; found: C:

53.19, H: 3.90, N: 12.00.

2-(2-(5-nitrofuran-2-yl)-4-oxoquinazolin-3(4H)- yloxy)acetohydrazide (19).

A solution of compound 18 (3.59g, 0.01 mol) and hydrazine hydrate (0.75 g, 0.015 mol) in ethanol (60 ml)

IJSEwas refluxedRfor 4h. The reaction mixture was

2-(5-nitrofuran-2-yl)-4-oxoquinazolin-3(4H)-yl acetate

(17).

A solution of the hydroxyl quinazolinone derivative 5 (2.73 g, 0.1 mol) in freshly distilled acetic anhydride (15 ml) was reflxed for 4 h. The mixture was concentrated
and the residue cooled recrystallized from benzene to
concentrated and then allowed to cool and the obtained
solid was filtered of and crystallized from dioxane to
form the hydrazide19.
Compound 19: Yield 71% (2.45 g), m.p.246-248oC, IR
:1607(C=N), 1658, 1681(C=O), 3189, 3274, 3332(NH,
NH2). 1H-NMR (CDCl ): 4.66 (s, 2H, OCH CO), 6.88-

R3R

R2R

produce the ester derivative 17.
Compound 17: Yield 76% (2.39 g), m.p.180-182oC, IR

8.44 (m, 6H, Ar-H, and furan-H), 9.23 (br, 2H, NHR2R, DR2RO

exchangeable), 10.14 (br., H, NH, DR2RO exchangeable).

:1609(C=N), 1667, 1701(C=O), 3254 (NH). 1H-NMR
MS: 345 (M.+). Anal. calc. for C H
N O (345): C: 48.70,

R14R

R11R

R5R

R6R

(CDCl3 ): 2.39(s, 3H, COCH3 ), 6.85- 8.40 (m, 6H, Ar-H, and furan-H). MS: 315 (M.+). Anal. calc. for C14 H9 N3 O6 (315): C: 53.33, H: 2.86, N: 13.33; found: C: 53.04, H: 3.15, N: 13.02.

Conclusion:

In this paper, the synthesized 2-(5-nitrofuran-2-yl)-4H- benzo[d][1,3]oxazin-4-one 2 was successfully converted into the more stable and the higher functionalized substituted quinazolinone derivatives through heterocyclic ring transformation. Also the plethora of research described in this manuscript indicates a wide spectrum of biological activities exhibited by the newly synthesized quinazolinone derivatives as antimicrobial agents.

Acknowledgement:

The authors are grateful to Prof. Dr. Fatma Farag , Biochemistry Department, Faculty of Science, Ain Shams University, for performing the biological activity for the
H: 3.19, N: 20.29; found: C: 49.01, H: 2.92, N: 19.98.
newly synthesized compounds.

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