Microwave assisted synthesis of pyridin-1-ium salt of 6-nitroquinazolin-4-one and its 6-amino analog under ultrasonic irradiation

Article abstract of DOI:10.14233/ajchem.2014.16697

The new compounds of quinazolin-4-one derivative i.e., 2-methyl-6-nitroquinazolin-4-one substituted pyridin-1-ium salt at methyl group and its 6-amino analog have been synthesized. Microwave irradiation of solution of 2-bromomethyl-6- nitroquinazolin-4-one and pyridine in acetonitrile for 3 min afforded 1-[(6-nitroquinazolin-4-one-2-yl)methyl]pyridin-1-ium bromide; and nitro reduction of the product with iron in ethanol/acetic acid/water under ultrasonic irradiation afforded 1-[(6-aminoquinazolin-4-one-2-yl)methyl]pyridin-1-ium bromide. The structure of the synthesized compounds were confirmed on the basis of FT-IR, ¹H NMR and ¹³C NMR data.

Full text of DOI:10.14233/ajchem.2014.16697

Asian Journal of Chemistry; Vol. 26, No. 23 (2014), 7904-7906
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.16697
Microwave Assisted Synthesis of Pyridin-1-ium Salt of 6-Nitroquinazolin-4-one
and its 6-Amino Analog under Ultrasonic Irradiation
1,*
1
2
1
HAYUN , A. ARRAHMAN , H. SURYADI and A. YANUAR
1Pharmaceutical Chemistry Laboratory, Faculty of Pharmacy, University of Indonesia, Depok 16424, West Java, Indonesia
2Microbiology Laboratory, Faculty of Pharmacy, University of Indonesia, Depok 16424, West Java, Indonesia
*Corresponding author: Fax: +62 21 7863433; Tel: +62 21 7270031; E-mail: hayun.ms@ui.ac.id
Received: 15 November 2013;
Accepted: 18 March 2014;
Published online: 15 November 2014;
AJC-16260
The new compounds of quinazolin-4-one derivative i.e., 2-methyl-6-nitroquinazolin-4-one substituted pyridin-1-ium salt at methyl group
and its 6-amino analog have been synthesized. Microwave irradiation of solution of 2-bromomethyl-6- nitroquinazolin-4-one and pyridine
in acetonitrile for 3 min afforded 1-[(6-nitroquinazolin-4-one-2-yl)methyl]pyridin-1-ium bromide; and nitro reduction of the product
with iron in ethanol/acetic acid/water under ultrasonic irradiation afforded 1-[(6-aminoquinazolin-4-one-2-yl)methyl]pyridin-1-ium bromide.
The structure of the synthesized compounds were confirmed on the basis of FT-IR, 1H NMR and 13C NMR data.
Keywords:Pyridinium salt, Quinazolin-4-one, 6-Nitroquinazolin-4-one, 6-Aminoquinazolin-4-one, Ultrasound,Aqueous media, Microwave.
and 13C NMR spectra were recorded on a NMR spectrometer
(JEOL JNM 500) using TMS as the internal standard. Physical
INTRODUCTION
4(3H)-Quinazolinone derivatives are the important class
of heterocycles. They possess various biological activities such
as antibacterial, antiinflammation, antihistaminic, etc., depend
data and analytical data of the synthesized compounds are
given in Tables 1 and 2, respectively.
on the substituents at the ring system1-3. On the other hands,
some of pyridium salts exhibit antibacterial acitivity. The
TABLE-1
PHYSICAL DATA OF THE SYNTHESIZED COMPOUNDS
pyridinium salts of phenacyl were obtained by the reaction of
phenacyl halide in chloroform at room temperature for over-
night at a dark place, while the pyridium salts of alkyl were
obtained by the reaction of corresponding alkyl halide and
pyridines in appropriate solvents, heated at reflux for 6-50
h4-6. Microwave (MW) and ultrasonic irradiation has attracted
considerable attention for rapid synthesis of organic comp-
ounds7-9. In this paper, we report the microwave assisted syn-
thesis of 1-[(6-nitroquinazolin-4-one-2-yl)methyl]pyridin-1-
ium bromide and synthesis of its 6-amino analog under ultra-
sonic irradiation.
Compound
Yield (%)
44.0
Form
m.p. (oC)
240-242
235-236
222-223
245-246
224-225
1
2
3
4
5
White crystalline powder
White crystalline powder
Yellow powder
54.0
82.5
94.0
White crystalline powder
Pale yellow powder
64.0
Synthesis of methyl-4(3H)-quinazolinone (1): Com-
pound 1 was synthesized under microwave irradiation
according to reported method10-11
.
Synthesis of 2-(bromomethyl-4(3H)-quinazolinone (2):
Compound 2 was synthesized by treatment of solution of 1
in dimethylformamide (DMF) with N-bromosuccinimide
(NBS)12.
EXPERIMENTAL
All the solvents, reagents and chemicals are analytical
grade and were used without purification. Microwave irradia-
tion was performed using modified home microwave oven
completed with reflux condensor. The purity of the products
was tested using TLC method. Melting points were determined
in capillary tube using melting point apparatus (Stuart Scien-
tific) and are uncorrected. Infrared (IR) spectra were recorded
on a FTIR spectrophotometer (8400S, Shimadzu) and 1H NMR
Synhtesis of 2-(bromomethyl)-6-nitro-4(3H)-quinazoli-
none (3): Compound 3 was synthesized by nitration of 2
according to reported method for nitro derivatives synthesis
of quinazolin-4-one13,14. To a solution of 2-(bromomethyl)-
4(3H)-quinazolinone (2, 6.93 g, 30 mmol) in concentrated
sulfuric acid 90 mL, fuming nitric acid (7.5 mL) was added
dropwise at 0 °C. The reaction mixture was stirred at room
temperature for 4 h and then poured into crushed ice (200 mL).

Vol. 26, No. 23 (2014)
Microwave Assisted Synthesis of Pyridin-1-ium Salt of 6-Nitroquinazolin-4-one 7905
TABLE-2
IR AND NMR DATA OF THE SYNTHESIZED COMPOUNDS
IR νmax (cm-1)
3,170 (N-H lactam), 3047 (ArC-H str), 2918 (AlC-H str), 11.75 broad (1H, s, NH), 8.28 (1 H, dd, J = 8.4; 1.9, H-5), 7,77 (1H, td, J =
NMR (δ, ppm)
Compd.
1
2
3
4
1,689 (C=O lactam), 1,612 (C=N)
8.2; 1,8, H-7), 7.68 (1H, d, J = 9.0, H-8), 7.48 (1H, t, J=8.4, H-6), 2.60
(3H, s, CH3)
3,175 (N-H lactam), 3,030 (ArC-H str), 2,924 (AlC-H
str), 1,689 (C=O lactam), 1,608 (C=N), 804 (C-Br)
12.58 broad (1H, s, NH), 8.11 (1 H, d, J = 10 Hz, H-5), 7.66 (1H, d, J =
7.8 Hz, H-8), 7.83 (1H, t, J = 7.1 Hz, H-6), 7.54 (1H, t, J = 7.8, H-7), 4,40
(2H, s, 2-CH2)
3,189 (NH lactam), 3,030 (ArC-H str), 2,924 (AlC-H
str), 1,682 (C=O lactam), 1,616 (C=N), 1,467 (CH2 sci),
1,577, 1,491 (ArC=C), 1,521, 1,342 (NO2), 795 (C-Br)
3,134 (N-H lactam), 3,045 (ArC-H str), 2,955-2,862 (Al
13.12 broad (1H, s, NH), 8.79 (1 H, d, J = 1.9 Hz, H-5), 8.56 (1H, dd, J =
8.2, 1.9 Hz, H-7), 7.87 (1H, d, J=9.0 Hz, H-8), 4,44 (2H, s, 2-CH2)
1H NMR: 13.30 broad (1H, s, NH); 9.16 (2H, d, J = 6.0 Hz, H-2’& H-6’),
C-H str), 1,699 (C=O lactam), 1,614 (C=N), 1,579, 1,493 8.79 (1 H, d, J = 2.2 Hz, H-5), 8.77 (1 H, t, J = 7.8 Hz, H-4’), 8.47 (1H,
(ArC=C), 1,464 (CH2 sci), 1,521, 1,348 (NO2) , 769, 717 dd, J = 10.0, 2.5 Hz, H-7), 8.29 (2H, t, J = 16 Hz, H-3’ & H-5’), 7.53 (1H,
d, J = 7.5 Hz, H-8), 6.04 (2H, s, 2-CH2-N+). 13C NMR: 160.67 (C=O
(C-H bend)
amide), 154.99 (-C=N), 151.62 (CAr-NO ), 146.75 (C-2 & C-6pyridine ring),
2
146,84 (C-4pyridine ring), 145.16 (CAr-N=C), 127.72 (C-3 & C-5pyridine ring), 128.76,
128.66, 121.99, 123.28 (Caromatic), 60.28 (Califatic
)
3423, 3298 (NH2), 3,134 (N-H lactam), 3,050 (ArC-H
1H NMR: 12.40 broad (1H, s, NH), 9.12 (2H, d, J = 6.0 Hz, H-2’ and H-
5
str), 2,960-2,858 (AlC-H str), 1,672 (C=O lactam), 1,633 6’), 8.73 (1 H, t, J = 7.8 Hz, H-4’), 8.24 (2H, t, J = 7.1 Hz, H-3’ and H-5’),
(C=N), 1,562, 1491 (ArC=C), 1,435 (CH2 sci), 794
(primary Ar-amine), 740, 694 (C-H bend)
7.15 (1 H, d, J = 2.6 Hz, H-5), 7.05 (1H, d, J = 9.1 Hz, H-8), 6.97 (1H, dd,
J = 7.5, 2.6 Hz, H-7), 5.83 (2H, s, 2-CH2-N+), 5.69 (2H, s, NH2). 13C NMR:
161.07 (C=O amide), 148.27 (-C=N), 146.52 (C-2 & C-6pyridine ring), 146.48
(CAr-NH ), 145,46 (C-4pyridine ring), 138.19 (CAr-N=C), 127.72 (C-3 & C-5pyridine
2
ring), 127.91, 122.25, 122.12, 106.24 (Caromatic), 60.15 (Califatic
)
A precipitate was filtered, washed with water and dried in
vacuum drying oven at 70 °C for 1 h.
to obtain 2-bromomethylquinazolin-4-one (2). Nitration of 2
with fuming nitric acid in concentrated sulfuric acid at room
temperature to obtain 2-bromomethyl-6-nitroquinazolin-4-one
(3) and then microwave irradiation of solution of 3 and pyridine
in acetonitrile at power level 30 % for 3 min to provide 1-[(6-
nitroquinazolin-4-one-2-yl)methyl]pyridin-1-ium bromide (4).
In the last step, suspension of 4 in mixture of ethanol, glacial
acetic acid and water was reduced with iron under sonication
at 30 °C for 1 h to get 1-[(6-aminoquinazolin-4-one-2-yl)methyl]-
pyridin-1-ium bromide (5).
1-[(6-Nitroquinazolin-4-one-2-yl)methyl]pyridin-1-
ium bromide (4): Solution of 3 (690 mg, 2.5 mmol) and
pyridine 2 mL in acetonitrile 150 mL was irradiated under
microwave for 3 min at power level 30 %. The precipitate
formed was filtered off, washed with cold acetonitrile and dried
in vacuum drying oven at 70 °C for 1 h.
1-[(6-Aminoquinazolin-4-one-2-yl)methyl]pyridin-1-
ium bromide (5): Compound 5 was synthesized by reduction
of 4 using modified method of aryl nitro reduction reported
by Gamble et al.9. To a suspension of 4 (182 mg, 0.5 mmol) in
a mixture of glacial acetic acid ( 1 mL), ethanol (2 mL) and
water (1 mL) was added reduced iron powder (0.140 g, 2.5
mmol). The resulting suspension was exposed to ultrasonic
irradiation for 1 h at 30 °C with TLC analysis monitoring for
the completion of the reaction. The reaction mixture was
filtered to remove the iron residue and the filtrate obtained
was diluted with ethanol and added concentrated ammonia
solution to precipitate iron salts. The resulting mixture was
filtered through cellite and solvent of the filtrate was evaporated
under reduced pressure. The crude residue was then recrys-
tallized from methanol.
The IR spectrum of the title compound 4 showed absor-
ption bands at 3,134 and 1,699 cm-1 due to the pesence of N-H
and C=O lactam, respectively; 3,045 cm-1 (aromatic C-H),
2,955-2,862 cm-1 (alipatic C-H), 1,614 cm-1 (C=N), 1,521 and
1,348 cm-1 (NO2). In the 1H NMR spectrum, a proton of NH
lactam appeared as one broad singlet at δ 13.30 ppm; and the
three protons of quinazolinone ring are observed as two
doublets at δ 8.79 ppm (1 H, J = 2.2 Hz, H-5) and at δ 7.53
ppm (1H, J = 7.5 Hz, H-8) and as one double doublet at δ 8.47
ppm (1H, J = 10, 2.5 Hz, H-7). Five protons of pyridine ring
are observed as one doublet at δ 9.16 ppm (2H, J = 6 Hz, H-2'
and H-6'), as two triplets at δ 8.29 ppm (2H, J = 16 Hz, H-3'
and H-5') and at δ 8.77 ppm (1 H, J = 7.8 Hz, H-4'), while two
protons of the methyl group appear as a singlet at δ 6.04 ppm
(2H, 2-CH2). The chemical shifts of proton of CH2 and pyridine
ring were observed very downfield than that of CH2 of
compound 3 and free pyridine15. These data indicated that
compound 4 was quarternized (pyridinium) alkyl halide 6. The
IR spectrum of compound 5 showed absorption band at 3,423,
3,298 and 794 cm-1, while the bands at 1,521 and 1,348 cm-1
disappeared. This data confirmed that nitro group of compound
RESULTS AND DISCUSSION
The titled compounds (4 and 5) were synthesized stepwise
summarized in Fig. 1. In the first step, anthranilic acid was
reacted with acetic anhydride (Ac2O) under microwave irra-
diation for 10 min at power level 30 %. Ammonium acetate
was added and the microwave irradiation at power level 30 %
was continued for 10 min to provide 2-methylquinazolinon-
4-one (1). This compound was then treated with NBS in DMF
1
4 was reduced to be primary amine group. In the H NMR
spectrum, two proton of primary amine appeared as singlet at

7906 Hayun et al.
Asian J. Chem.
O
O
O
OH
NH
Ac2O
Amm. Acetate
O
(1)
MW,
Power level 30%,
10 mnt.
MW,
Power level 30%,
10 mnt.
NH2
N
N
(3)
Anthranilic Acid
NBS, DMF, rt.
Stir, 18 h.
O
O
O2N
HNO3 fuming/H2SO4 pkt
rt, 4 h.
NH
NH
(2)
(3)
N
CH2Br
N
CH2Br
N
Acetonitrile,
MW,
Power level 30%,
3 mnt.
O
O
H2N
O2N
NH
Fe (s), EtOH/AcOH/H2O
NH
N
Sonication, 30 oC, 1 h.
N
Br-
Br-
N+
(5)
N+
(4)
Fig. 1. Schematic reaction of the synthesis of the titled compounds (4 and 5)
δ 5.69 ppm (2H, NH2). 13C NMR spectra of compound 4 and
5 as indicated in Table-1 confirmed the proposed structures.
2. S.R. Pattan, Indian J. Chem., 45B, 1778 (2006).
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1055 (2009).
Conclusion
4. S. Hameed, M. Saeed, A. Khan, M. Ahmed, S.S. Nizami and M.H.
Kazmi, J. Islamic Ac. Sci., 7, 26 (1994).
In conclusion, reactions of 2-(bromomethyl)-6-nitro-
quinazolin-4-one and pyridine in acetonitrile under microwave
irradiation at power level 30 % for 3 min afforded 1-[(7-nitro-
1-oxo-1,2-dihydroisoquinolin-3-yl)methyl]pyridin-1-um (4)
and the reduction of 4 with iron powder in mixture of ethanol,
glacial acetic acid and water under sonication irradiation for
1 h afforded 1-[(7-amino-1-oxo-1,2-dihydroisoquinolin-3-
yl)methyl]pyridin-1-um (5).
5. R.N. Jayatissa, R.P. Perera, C.M. Hettiarachchi and P.M. Weerawarna,
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6. V.Alptüzün, S. Parlar, H. Tasli and E. Erciyas, Molecules, 14, 5203 (2009).
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ACKNOWLEDGEMENTS
12. C.M. Gupta, A.P. Bhaduri and N.M. Khanna, J. Med. Chem., 11, 392
(1968).
The authors thank the Directorate of Research and
Community Service, University of Indonesia, Depok, Indonesia,
for the financial support of this research; and also to Research
Center for Chemistry of the Indonesian Institute of Science,
Serpong, Indonesia, for recording NMR spectral data.
13. Y. Kabri, P. Verhaeghe, A. Gellis and P. Vanelle, Molecules, 15, 2949
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