Cynogen bromide and ethylacetoacetate in heterocyclization: Novel synthesis of tetracyclic derivative of 3-aryl quinazolinones

Article abstract of DOI:10.1002/jhet.440

(Chemical Equation Presented) In this work, tricyclic 1-amino-4- (substituted phenyl)[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one 3 was synthesized by treatment of 2-hydrazinyl-3-(substituted phenyl)quinazolin-4(3H)-one 2 with cyanogen bromide, which on cyc

Full text of DOI:10.1002/jhet.440

1144
Cynogen Bromide and Ethylacetoacetate in Heterocyclization:
Novel Synthesis of Tetracyclic Derivative of 3-Aryl
Quinazolinones
Vol 47
M. B. Deshmukh,a Suresh S. Patil,b* Sanjeevani S. Patil,b and Swati D. Jadhavb
aDepartment of Organic Chemistry/AGPM, Shivaji University, Kolhapur, Maharashtra, India
bDepartment of Chemistry, PDVP Mahavidyalaya, Tasgaon, Maharashtra 416312, India
*E-mail: sanyujapatil@yahoo.com
Received September 23, 2009
DOI 10.1002/jhet.440
Published online 26 July 2010 in Wiley Online Library (wileyonlinelibrary.com).
In this work, tricyclic 1-amino-4-(substituted phenyl)[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one 3 was
synthesized by treatment of 2-hydrazinyl-3-(substituted phenyl)quinazolin-4(3H)-one 2 with cyanogen
bromide, which on cyclization with ethylacetoacetate to get the targeted fused tetracyclic derivatives of
quinazoli-4(3H)one 4. The synthesized compounds have been characterized using IR and 1H NMR,
mass spectral data together with elemental analysis.
J. Heterocyclic Chem., 47, 1144 (2010).
INTRODUCTION
mation of which has been explained by the appearance
of IR band at 3390–3300 cmꢀ1 due to ANHNH2 and
disappearance of singlet displayed at d, 10–11 ppm due
to ASH and two additional singlets appeared between d,
9–11 and d, 2–6 ppm due to ANH and ANH2 protons,
respectively, in their PMR spectra. The condensation of
2 with cyanogens bromide in absolute alcohol gave the
corresponding desired tricyclic amino triazoles 3a–g; the
formation of which was confirmed by the observation of
a broad IR band at 3420–3000 cmꢀ1 and singlet
between d, 3–6 ppm due to ANH2 protons in their PMR
spectrum. The compounds 3a–g were cyclocondensed
with ethylacetoacetate to get the targeted tetracyclic
compounds 4a–g. The formation of 4 has been estab-
lished by the disappearance of singlet between d, 3–6
due to ANH2 protons and appearance of additional sin-
glets due to ArACH3 and ¼¼CH in their PMR spectrum.
Quinazoline derivatives have attracted considerable
attention due to their significant biological activities
[1,2], especially antifungal [3,4], insecticidal [5], antihis-
taminic [6], anti-inflammatory [7], antibacterial [8], anti-
convulsant [9,10], antithrombotic [11], antitubercular
[12], and antitumor [13]. In this article, we report a new
route for the synthesis of triazolo and tetracyclic deriva-
tives of quinazolinone.
RESULT AND DISCUSSION
The new triazolo and tetracyclic derivatives of quina-
zolinone were prepared following the reaction sequences
depicted in Scheme 1 and supported mechanism in
Scheme 2. The starting compound 1 was prepared by se-
quential treatment of anthranilic acid with thiocarbamate
salts of substituted aniline and carbon disulphide accord-
ing to the reported method [14]. The appearance of
broad band at 3330–3110 cmꢀ1 in IR spectrum and a
singlet displayed at d, 10–11 ppm in the PMR spectrum
due to ASH supports their formation. Compounds 1a–g
were heated with excess hydrazine hydrate to form 2-
hydrazino derivatives 2a–g in good yield [15]; the for-
EXPERIMENTAL
All melting points reported are incorrect and were deter-
mined by open capillary method. All chemicals used were of
A.R. grade and have been used without further purification. IR
spectra (in KBr, cmꢀ1) were recorded on a Perkin-Elmer 783
(FTIR) spectrophotometer. 1H NMR spectra recorded in
C
V
2010 HeteroCorporation

September 2010 Cynogen Bromide and Ethylacetoacetate in Heterocyclization: Novel Synthesis
of Tetracyclic Derivative of 3-Aryl Quinazolinones
1145
Scheme 1
2-Hydrazinyl-3-(4-methoxyphenyl)quinazolin-4(3H)-one
(2a). A compound la (4.824 gm, 0.018 mol) was refluxed with
5 mL hydrazine hydrate in ethanol (15 mL) with constant stir-
ring at 100ꢁC for about 1.5 h, then cooled and thus the solid
obtained was recrystallized from ethanol to furnish 2a [15],
yield, 4.118 gm (86%), m.p. 207ꢁC, IR: 3386–3328, 1664
cmꢀ1 1H NMR (CDCl3): d (ppm), 2.65 (s, 3H, ArACH3),
.
6.25(s, 2H, ANH2), 6.9–8.1 (m, 8H, ArAH), 10.9 (s, 1H, br,
ANH); ms: m/z 282(12), 266(26), 251(45), 175(100), 107(55),
31(10). Anal. Calcd. for C15H14O2N4 (266): C, 63.82%; H,
5.00%; N, 19.85%. Found: C, 63.89%; H, 5.04%; N, 19.81%.
1-Amino-4-(4-methoxyphenyl)[1,2,4]triazolo[4,3-a]quina-
zolin-5(4H)-one (3a). A compound 2a (5.054 gm, 0.019
mole) in ethanolic NaOH (50 mL) and cyanogen bromide (1
cm3, 0.019 mole) were stirred for 3 h at room temperature. Af-
ter neutralization of it with 10% sodium bicarbonate, the solid
obtained was filtered and further recrystallized from ethanol to
give 3a, yield, 4.423 gm (80%), m.p. 270ꢁC. IR: 3420–3010,
1
1685, 1615 cmꢀ1. H NMR (DMSO-d6): d (ppm), 2.56 (s, 3H,
ArACH3), 5.62 (s, 2H, ANH2), 7.1–8.2 (m, 8H, ArAH); ms:
m/z 307(50), 291(20), 276(62), 200(100), 107(72), 31(16).
Anal. Calcd. for C16H13ON5 (291): C, 62.53%; H, 4.26%; N,
22.79%. Found: C, 62.61%; H, 4.32%; N, 22.71%.
Scheme 2
CDCl3/DMSO-d6 were scanned on a Bruker A-300 F-NMR
spectrometer (Table 1). TMS was used as an internal standard
with chemical shifts d in ppm from down field to up field.
Mass spectra were analyzed by EI technique on Shimadzu QP
2010 PLUS GC-MS system. The purity of products, in addi-
tion to the elemental analysis (Table 2), was checked by
TLC.
3-(4-Methoxyphenyl)-2-sulfanylquinazolin-4(3H)-one (1).
These compounds were prepared according to the reported
method [14].
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1146
M. B. Deshmukh, S. S. Patil, S. S. Patil, and S. D. Jadhav
Vol 47
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2010 Cynogen Bromide and Ethylacetoacetate in Heterocyclization: Novel Synthesis
of Tetracyclic Derivative of 3-Aryl Quinazolinones
1147
Table 2
Characterization data of compounds 2, 3, and 4.
Calcd (%) (Found)
Compound
R groups
m.p. (ꢁC)
209
Yield (%)
86
Molecular formula
C15H14ON4
C
H
N
2b
o-CH3
67.65
(67.59)
67.65
(67.58)
67.65
5.30
(5.38)
5.30
(5.25)
5.30
21.04
(21.10)
21.04
(21.12)
21.04
2c
2d
2e
2f
m-CH3
p-CH3
p-Cl
211
205
218
222
196
269
272
265
278
281
276
308
307
302
312
310
314
86
76
82
82
83
78
68
72
70
69
73
70
68
69
73
70
61
C15H14ON4
C15H14ON4
(67.72)
58.65
(5.35)
3.87
(21.09)
19.54
C14H11ON4Cl
C14H11ON4Cl
C14H11ON4Br
C16H13ON5
(58.58)
58.65
(4.95)
3.87
(19.47)
19.54
m-Cl
(58.55)
50.78
(4.80)
3.35
(19.60)
16.92
2g
3b
3c
3d
3e
3f
p-Br
(50.62)
65.97
(65.91)
65.97
(66.06)
65.97
(65.98)
57.80
(3.40)
4.50
(4.58)
4.50
(4.44)
4.50
(4.49)
3.23
(16.86)
24.04
(24.16)
24.04
(24.12)
24.04
(23.99)
22.47
o-CH3
m-CH3
p-CH3
p-Cl
C16H13ON5
C16H13ON5
C15H10ON5Cl
C15H10ON5Cl
C15H10ON5Br
C20H15O2N5
C20H15O2N5
C20H15O2N5
C19H12O2N5Cl
C19H12O2N5Cl
C19H12O2N5Br
(57.73)
57.80
(3.12)
3.23
(22.38)
22.47
m-Cl
(57.71)
50.58
(3.11)
2.83
(22.51)
19.66
3g
4b
4c
4d
4e
4f
p-Br
(50.65)
67.22
(2.91)
4.23
(19.51)
19.60
o-CH3
m-CH3
p-CH3
p-Cl
(67.16)
67.22
(67.11)
67.22
(67.27)
60.41
(60.36)
60.41
(4.11)
4.23
(4.18)
4.23
(4.22)
3.20
(3.14)
3.20
(19.52)
19.60
(19.69)
19.60
(19.69)
18.54
(18.48)
18.54
m-Cl
(60.50)
54.04
(54.11)
(3.12)
2.86
(2.77)
(18.48)
16.59
(16.64)
4g
p-Br
[3] Alagarsamy, V.; Giridhar, R.; Yadav, M. R.; Revati, R.;
Ruckmani, K.; Chercq, E. D. Indian J Pharm Sci 2006, 68, 532.
[4] Ghorab, M. M. Farmaco 2000, 55, 249.
[5] Singh, T.; Sharma, S.; Kishore, V.; Shrivastava, K. A.
Indian J Chem 2006, B45, 2558.
Fused tetracyclic quinazolin-4(3H)one (4a). A mixture of
3a (2.91 gm, 0.01 mole), ethylacetoacetate (12.7 cm3, 0.01
mole) and glacial acetic acid (20 mL) was refluxed for 4 h.
The solution was concentrated, cooled, and the crude product
obtained was recrystallized from chloroform:n-hexane (50% v/
v) mixture, yield, 2.570 gm (72%), m.p. 310ꢁC. IR: 1725–
[6] Raju, M. B.; Singh, S. D.; Raghu, R. R. A.; Rajan, K. S.
Indian J Pharm Sci 2007, 69, 853.
1
1690 broad, 1662 cmꢀ1, 1625. H NMR (DMSO-d6) d (ppm):
[7] Yadav, M. R.; Shirude, S. T.; Parmar, A.; Balaraman, R.;
Giridhar, R. J Heterocycl Compd 2006, 42, 1038.
[8] Alagarsamy, V.; Pathak, U. S.; Goyal, R. K. Indian J Pharm
Sci 2000, 62, 63.
2.44 (s, 3H, ArACH3), 2.47 (s, 3H, ArACH3), 6.21 (s, 1H,
¼¼CH), 7.2–8.4 (m, 8H, ArAH); ms: m/z 373(45), 342(55),
266(100), 107(35), 31(15). Anal. Calcd. for C20H15O2N5
(357): C, 64.34%; H, 4.05%; N, 18.76%. Found: C, 64.27%;
H, 4.11%; N, 18.79%.
[9] Ghany, A. E. A.; Hemeda, A. W. M. Acta Pharm 2003, 53,
127.
[10] El-Helby, A. G. A. Acta Pharm 2003, 53, 127.
[11] Demer, J. P. J Heterocycl Chem 1989, 26, 1535.
[12] Kunes, J. Farmaco 2001, 55, 725.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet