A facile synthesis of 2,3-disubstituted Pyrido[2,3-h]quinazolin-4(3H)-ones

Article abstract of DOI:10.1081/SCC-120002007

Synthesis of 2-substituted-4H-Pyrido[2,3-h]benzoxazin-4-ones (2) from 5-Aminoquinoline-6-carboxylic acid (1) and their conversion to 2,3-disubstituted Pyrido[2,3-h]quinazolin-4(3H)-ones(3) is reported.

Full text of DOI:10.1081/SCC-120002007

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
A FACILE SYNTHESIS OF 2,3-DISUBSTITUTED
PYRIDO[2,3-h]QUINAZOLIN-4(3H)-ONES
T. Aruna Kumari , M. Satyanarayana Reddy & P. Jaya Prasad Rao
To cite this article: T. Aruna Kumari , M. Satyanarayana Reddy & P. Jaya Prasad Rao (2002) A
FACILE SYNTHESIS OF 2,3-DISUBSTITUTED PYRIDO[2,3-h]QUINAZOLIN-4(3H)-ONES, Synthetic
Communications, 32:2, 235-240, DOI: 10.1081/SCC-120002007
To link to this article: http://dx.doi.org/10.1081/SCC-120002007
Published online: 16 Aug 2006.
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SYNTHETIC COMMUNICATIONS, 32(2), 235–240 (2002)
A FACILE SYNTHESIS
OF 2,3-DISUBSTITUTED
PYRIDO[2,3-h]QUINAZOLIN-4(3H)-ONES
T. Aruna Kumari, M. Satyanarayana Reddy,
and P. Jaya Prasad Rao*
Department of Chemistry, Osmania University,
Hyderabad, 500 007, A. P., India
ABSTRACT
Synthesis of 2-substituted-4H-Pyrido[2,3-h]benzoxazin-4-ones
(2) from 5-Aminoquinoline-6-carboxylic acid (1) and their con-
version to 2,3-disubstituted Pyrido[2,3-h]quinazolin-4(3H)-
ones(3) is reported.
5-Aminoquinoline-6-carboxylic acid,1 inspite of its wide potential
has been scarcely used in the synthesis of heterocyclic synthesis. It has
been successfully used by us2 for the preparation of 2-methyl-
4H-pyrido[2,3-h]quinazolin-4(3H)-one. Here in we report the synthesis
of 2-aryl-4H-pyrido[2,3-h]benzoxazin-4-ones (2a–d) and 2,3-disubstituted
pyrido[2,3-h]quinazolin-4(3H)-ones (3a–s).
The reaction of 5-aminoquinoline-6-carboxylic acid (1) with 4-methyl-
benzoyl chloride in pyridine at 0ꢀC gave a crystalline compound in high
yield. The mass spectrum of the compound revealed the molecular ion
*Corresponding author.
235
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

ORDER
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236
ARUNA KUMARI, SATYANARAYANA REDDY, AND PRASAD RAO
at m/z 288 indicating to be a 1:1 product formed by the elimination of
hydrogen chloride and water. The IR spectrum (KBr) showed the absence
1
of NH and presence of a d-lactonic carbonyl at 1758 cmꢁ1. The H-NMR
spectrum (DMSO-d6) exhibited signals at d 2.5 (s, 3H, CH3), 7.4 (d, 2H,
Ar-H of H7, H8), 7.7 (m, 1H, Ar-H of H4), 8.2(d, 1H, Ar-H of H 5), 8.4 (m,
3H, Ar-H of H2, H6, H9), 9.2(d, 1H, Ar-H of H 1), 9.4 (d, 1H, Ar-H of H3).
Based on the spectral and analytical data the compound has been charac-
terised at 2-(4-methylphenyl)-4H-pyrido[2,3-h]3,1-benzoxazin-4-one (2c).
This reaction was extended to three other aroyl chlorides and the
products obtained were characterised as 2-aryl-4H-pyrido[2,3-h]3,1-benzo-
xazin-4-ones (2a–d) (Table 1) by analogy and on the basis of spectral and
analytical data (Tables 1–3). Attempts to isolate N-acylamino acid in the
reaction of 1 with aroyl chlorides were not successful.
Compounds 2exhibited intense molecular ions in their mass spectra.
The mass spectral fragmentation is characterised by the presence of ions
.
ꢂ
ꢂ
corresponding to the loss of Ar, CO2. In addition, Ar and ArCO fragment
ions have been observed.
Compounds 2possess a labile lactone ring which can readily undergo
reaction with nucleophiles involving replacement of oxygen in the ring. Thus
reaction of 2a with 4-methylaniline in acetic acid afforded a crystalline
compound, identified as 2-phenyl-3-(4-methylphenyl)pyrido[2,3-h]quina-
zolin-4(3H)-one (3c) on the basis of mass (MþÁ at m/z 363), IR (KBr,
uC¼O at 1670 cmꢁ1) and 1H-NMR (DMSO-d6) spectral data [d 2.4 (s,
3H, CH3), 7.0–7.4 (m, 9H, Ar-H of C-aryl and N-aryl), 7.6 (m, 1H, Ar-H
of H2), 8.1 (d, 1H, Ar-H of H4), 8.5 (d, 1H, Ar-H of H5), 9.1 (d, 1H, Ar-H of
H1) and 9.3 (d, 1H, Ar-H of H3)]. The reaction of 2a was extended to
aniline, 4-nitroaniline and 2-methylanilines and the corresponding 3
(Table 1) were obtained in good yields.

ORDER
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PYRIDO[2,3-h ]QUINAZOLIN-4(3H)-ONES
237
Table 1. Characterisation Data of 2-Substituted-4H-pyrido[2,3-h]-3,1-benzoxazin-
4-ones (2) and 2,3-Disubstituted Pyrido[2,3-h]-quinazolin-4-(3H)-ones(3)
Compound
Ar
R
M.P. (ꢀC)
Yield (%)
80
2
a
6H5
C
–
–
–
204
2
215
258
>300
>300
260
254
>300
278
>300
288
>300
195
>300
238
>300
188
140
2b
2c
2d
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
4-Cl-C6H4
4-CH3-C6H4
4-OCH3-C6H4
C6H5
2
0
72
80
82
78
75
80
80
75
78
75
82
80
78
74
76
80
72
82
76
75
80
–
C6H5
C6H5
C6H5
C6H5
4-NO2-C6H4
4-CH3-C6H4
2-CH3-C6H4
C6H5
4-NO2-C6H4
4-CH3-C6H4
2-CH3-C6H4
C6H5
4-NO2-C6H4
4-CH3-C6H4
2-CH3-C6H4
C6H5
4-NO2-C6H4
4-CH3-C6H4
2-CH3-C6H4
H
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-CH3-C6H4
4-CH3-C6H4
4-CH3-C6H4
4-CH3-C6H4
4-OCH3-C6H4
4-OCH3-C6H4
4-OCH3-C6H4
4-OCH3-C6H4
4-CH3-C6H4
4-CH3-C6H4
4-CH3-C6H4
196
>300
228
230
CH2Ph
CH3
Likewise the reaction of all other 2-aryl-4H-pyrido[2,3-h]-3,1-benzo-
xazin-4-ones (2b–d) with aromatic primary amines in acetic acid also afforded
the corresponding 3 (Table 1) characterized by analogy and on the basis of
spectral and analytical data (Tables 1–3). The above reaction constitutes

ORDER
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238
ARUNA KUMARI, SATYANARAYANA REDDY, AND PRASAD RAO
Table 2. 1H NMR Data of 2and 3 (DMSO-d )
6
Compound
2b
1H NMR Data (d)
7.5 (d, 2H, Ar-H of H7, H8), 7.7 (m, 1H, Ar-H of H4), 8.2(d, 1H,
Ar-H of H5), 8.4 (m, 3H, Ar-H of H2, H6, H9), 9.1 (d, 1H, Ar-H of
H1), 9.4 (d, 1H, Ar-H of H3).
2.5 (s, 3H, CH3), 7.4 (d, 2H, Ar-H of H7, H8), 7.7 (m, 1H, Ar-H of
H4), 8.2(d, 1H, Ar-H of H 5), 8.4 (m, 3H, Ar-H of H2, H6, H9), 9.2(d,
1H, Ar-H of H1), 9.4 (d, 1H, Ar-H of H3).
7.1–7.5 (m, 10H, Ar-H of C-aryl and N-aryl), 7.6 (m, 1H, Ar-H of
H2), 8.1 (d, 1H, Ar-H of H4), 8.5 (1H, Ar-H of H5), 9.1 (d, 1H, Ar-H
of H1), 9.4 (d, 1H, Ar-H of H3).
7.2–7.6 (m, 10H, Ar-H of C-aryl & N-aryl and H2), 8.2(d, 1H, Ar-H
of H4), 8.5 (d, 1H, Ar-H of H5), 9.1 (d, 1H, Ar-H of H1), 9.4 (d, 1H,
Ar-H of H3).
2.4 (s, 3H, CH3), 7.0–7.4 (m, 9H, Ar-H of C-aryl & N-aryl), 7.6 (m,
1H, Ar-H) of H2), 8.1 (d, 1H, Ar-H of H4), 8.5 (d, 1H, Ar-H of H5),
9.1 (d, 1H, Ar-H of H1), 9.3 (d, 1H, Ar-H of H3).
2.1 (s, 3H, CH3), 7.1–7.5 (m, 9H, Ar-H of C-aryl & N-aryl), 7.7 (m,
1H, Ar-H of H2), 8.1 (d, 1H, Ar-H of H4), 8.4 (d, 1H, Ar-H of H5),
9.1 (d, 1H, Ar-H of H1), 9.4 (d, 1H, Ar-H of H3).
2.1 (s, 3H, CH3), 7.1–7.4 (m, 8H, Ar-H of C-aryl & N-aryl), 7.6 (m,
1H, Ar-H) of H2), 8.1 (d, 1H, Ar-H of H4), 8.5 (d, 1H, Ar-H of H5),
9.1 (d, 1H, Ar-H of H1), 9.4 (d, 1H, Ar-H of H3).
2.1 (s, 3H, ortho CH3), 2.3 (s, 3H, para CH3), 7.0–7.4 (m, 8H, Ar-H
of C-aryl & N-aryl), 7.7 (m, 1H, Ar-H of H2), 8.1 (d, 1H, Ar-H of
H4), 8.5 (d, 1H, Ar-H of H5), 9.1 (d, 1H Ar-H of H1), 9.4 (d, 1H,
Ar-H of H3).
2c
3a
3b
3c
3d
3h
3l
3m
3o
3.9 (s, 3H, OCH3), 7.0–7.6 (m, 10H, Ar-H of C-aryl & N-aryl and
H2), 8.2(d, 1H, Ar-H of H 4), 8.8 (d, 1H, Ar-H of H5), 9.1 (d, 1H, Ar-
H of H1), 9.3 (d, 1H, Ar-H of H3).
2.5 (s, 3H, CH3), 3.9 (s, 3H, OCH3) 7.1–7.3 (m, 8H, Ar-H of C-aryl &
N-aryl), 7.7 (m, 1H, Ar-H of H2), 8.1 (d, 1H, Ar-H of H4), 8.3 (d, 1H,
Ar-H of H5), 9.1 (d, 1H, Ar-H of H1), 9.3 (d, 1H, Ar-H of H3).
a simple one-step synthesis for a variety of pyrido[2,3-h]quinazolin-4-(3H)-
ones (3). Pyrolysis of 2with aromatic primary amines also resulted in corres-
ponding 3. However, the yields were relatively low. The formation of 3 from 2
probably involves nucleophilic attack by anilino nitrogen on carbonyl carbon
of the latter, resulting in an open chain intermediate. Subsequent loss of
elements of water from the tautomeric form of the intermediate yields 3. All
the 3 exhibited intense molecular ions in their mass spectra indicating the
stability of ring system. Generally MþÁ or MþÁ ꢁ 1 is observed as the base peak.

ORDER
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PYRIDO[2,3-h ]QUINAZOLIN-4(3H)-ONES
Table 3. Analytical Data of 2and 3
Found % (Calc.)
239
Compound
Molecular Formula
C
H
N
2
2
2
2
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
a
b
c
d
17H10N22O2
17H9N2O2Cl
18H12N2O2
18H12N2O3
C23H15N3O
C23H14N4O3
C24H17N3O
C24H17N3O
C
C
74.42 (74.45)
66.10 (66.13)
3.62 (3.65)
2.89 (2.92)
4.16 (4.17)
3.97 (3.95)
4.28 (4.30)
3.57 (3.55)
4.66 (4.68)
4.69 (4.68)
3.66 (3.65)
3.06 (3.03)
4.05 (4.03)
4.01 (4.03)
4.66 (4.68)
3.94 (3.92)
5.06 (5.04)
5.06 (5.04)
4.46 (4.49)
3.79 (3.77)
4.85 (4.83)
4.80 (4.83)
4.51 (4.53)
5.01 (5.04)
4.96 (4.98)
10.20 (10.22)
9.06 (9.08)
9.73 (9.72)
C 75.03 (75.00)
C
71.02 (71.05)
79.10 (79.08)
70.07 (70.05)
79.30 (79.34)
79.37 (79.34)
71.97 (71.97)
64.39 (64.41)
72.44 (72.45)
72.48 (72.45)
79.32(79.34)
70.56 (70.59)
79.54 (79.58)
79.57 (79.58)
75.98 (75.99)
67.93 (67.92)
76.31 (76.34)
76.31 (76.34)
75.23 (75.26)
79.56 (79.58)
75.72(75.75)
9.23 (9.21)
12.00 (12.03)
14.19 (14.21)
11.57 (11.57)
11.55 (11.57)
10.98 (10.95)
13.09 (13.07)
10.59 (10.57)
10.56 (10.57)
11.56 (11.57)
13.72 (13.73)
11.11 (11.14)
11.12(11.14)
11.06 (11.08)
13.18 (13.21)
10.70 (10.69)
10.71 (10.69)
14.61 (14.63)
11.11 (11.14)
13.92(13.95)
C23H14N3OCl
C23H13N4O3Cl
C24H16N3OCl
C24H16N3OCl
C24H17N3O
C24H16N4O3
C25H19N3O
C25H19N3O
C24H17N3O2
C24H16N4O4
C25H19N3O2
C25H19N3O2
C18H13N3O
C25H19N3O
C19H15N3O
Condensation of 2c with ammonia, methylamine and benzylamine
afforded the corresponding pyridoquinazolin-4-(3H)-ones (3q–s). Com-
pound 3s on treatment with aniline in acetic acid resulted in 3i. The ready
replacement of the methylamino moiety by phenylamino component in the
above reaction may be attributed to the enhanced conjugation in the
resulting product. The formation of 3i from 3s probably involves nucleo-
philic attack by anilino nitrogen on carbonyl carbon of the latter, resulting
in an open chain intermediate. Subsequent loss of elements of methylamine
from the tautomeric form of the intermediate yields 3i. The 3-unsubstituted
(3q) and 3-benzyl (3r) 2-(4-methylphenyl) pyrido[2,3-h]quinazolin-4(3H)-
ones proved to be exceptional in their reaction with aniline. In both
cases replacement of nitrogen function did not occur. Thus ring NH and
NCH2Ph are found to be resistant to replacement by NPh, which may
be attributed to relatively less electrophilic nature of carbonyl carbon in

ORDER
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ARUNA KUMARI, SATYANARAYANA REDDY, AND PRASAD RAO
the former (3q) and due to tautomerism in N–H free compound and to steric
factors in 3r.
EXPERIMENTAL SECTION
Melting points are uncorrected. IR spectra were recorded in KBr on a
Perkin-Elmer 1605 spectrophotometer, 1H-NMR (200 MHz) spectra on
Varian Gemini-200 spectrometer using TMS as internal standard and
mass spectra on Micromass 70-70H instrument.
2-Aryl-4H-pyrido[2,3-h]benzoxazin-4-ones (2): 5-Aminoquinoline-6-
carboxylic acid (1, 1 mmol) was dissolved in pyridine (5 ml) and cooled at
0ꢀC. To this the appropriate aroyl chloride (1 mmol) was added dropwise
with stirring and stirred for 2h. The mixture was poured into ice-cold
water (25 ml) and the compound separated was filtered, washed with small
volumes of cold water and few drops of ethanol and dried. The chara-
cterisation data of crystalline compounds 2thus obtained are included in
Tables 1–3.
Condensation of 2 with Primary Amines: A mixture of appropriate 2
(1 mmol), primary amine (1 mmol) and glacial acetic acid (5 ml) was heated
on steam bath for 5 h. The reaction mixture was cooled and poured into
water (25 ml) with stirring. The compound separated was filtered, washed
with small volumes of cold water and few drops of ethanol and dried. The
characterisation data 2,3-disubstituted pyrido[2,3-h]-quinazolin-4-(3H)-
ones(3) thus obtained are given in Tables 1–3.
IR spectra of 2showed uC¼O around 1750 cmꢁ1 while those of 3
exhibited around 1670 cmꢁ1
.
ACKNOWLEDGMENT
One of the authors (TAK) is thankful to the UGC, New Delhi, for the
award of a senior research fellowship.
REFERENCES
1. Bogert, M.T.; Fisher, H.L. J. Am. Chem. Soc. 1912, 34, 1570.
2. Satyanarayana Reddy, M.; Ratnam, C.V. Ind. J. Chem. 1983, 22B, 1100.
Received in the UK June 12, 2000

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