A novel approach for the one-pot synthesis of linear and angular fused quinazolinones

Article abstract of DOI:10.1016/j.tetlet.2011.04.019

A convenient and inexpensive one step methodology has been developed for the synthesis of linear and angular fused quinazolinones. The protocol, which uses amino heterocycles and o-bromo benzyl/naphthyl bromides as reactants, CuI as catalyst, Cs₂

Full text of DOI:10.1016/j.tetlet.2011.04.019

Tetrahedron Letters 52 (2011) 3033–3037
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel approach for the one-pot synthesis of linear and angular fused
quinazolinones
Arindam Maity, Shyamal Mondal, Rupankar Paira, Abhijit Hazra, Subhendu Naskar, Krishnendu B. Sahu,
⇑
Pritam Saha, Sukdeb Banerjee, Nirup B. Mondal
Department of Chemistry, Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, 4 Raja S C Mullick Road, Jadavpur, Kolkata 700 032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient and inexpensive one step methodology has been developed for the synthesis of linear and
Received 25 February 2011
Revised 29 March 2011
Accepted 1 April 2011
Available online 9 April 2011
angular fused quinazolinones. The protocol, which uses amino heterocycles and o-bromo benzyl/naph-
thyl bromides as reactants, CuI as catalyst, Cs2CO3 as base, L-proline as ligand, and DMF as solvent, pro-
ceeds via nucleophilic aromatic substitution of the N-heteroaromatic cationic intermediate followed by
in situ aerial oxidation at the benzylic position to the quinazolinone scaffold.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
CuI
L
-Proline
Cs2CO3
Linear and angular annulated
quinazolinones
Research in heterocyclic chemistry has gained momentum in re-
cent times because more than half of the biologically active mole-
cules belong to various classes of heterocycles.1 1,3-Diaza-
heterocycles like pyrimidine and quinazoline belong to a special
category as a sizeable number of fused pyrimidine derivatives, qui-
nazolinones in particular, have been identified as potential drug
molecules against various types of diseases. Innumerable quinaz-
olinone alkaloids isolated from plants, animals, and microorgan-
isms show different types of pharmacological activities.2
Rutaecarpine (1) and evodiamine (2) (Fig. 1), alkaloidal constituents
of the Chinese herbal drugs Wu-chu-ru3 and Shih-Hu,4 contain the
quinazolinone ring system in their structures. The unique scaffold
and pharmacological properties associated with these types of
compounds attracted the attention of chemists toward the synthe-
ses of various types of analogs and this led to the identification of
novel quinazolinone derivatives showing a wide variety of activities
like anti-inflammatory, antiallergic,5 anticonvulsant,6 sedative-
hypnotic,7 antihypertensive,8 and also anticancer.9
Hartwig cross-coupling reaction with amino-pyridines has been
performed to form the dipyridopyrimidones.14 However, in most
of the reported methods the presence of a keto functional group
was a prerequisite in the substrates or the reactants and this re-
quired multi-step reaction conditions. Hence the development of
a shorter and elegant synthetic route for this type of bioactive qui-
nazolinone scaffolds and of its analogs or precursors has become a
challenging task of current interest.15
As a part of our ongoing endeavor for the construction of struc-
turally unique heteroaromatics,16 we have developed a one step
methodology using amino heterocycles and o-bromo benzyl/naph-
thyl bromides as reactants to produce N-heteroaromatic cationic
intermediates, which upon base catalyzed nucleophilic aromatic
substitution followed by in situ aerial oxidation at the benzylic
position smoothly furnished the quinazolinone scaffold. The
results are reported herein.
At the outset, 2-aminopyridine (3a) and o-bromobenzyl
bromide (4a) were condensed by heating in dry DMF at 85 °C for
almost 6 h followed by addition of CuI (10 mol %) and K2CO3
The syntheses so far reported in the literature involve reactions
of anthranilamide with cyclic anhydrides10 or beta-diketones,11 of
2-aminobenzyl carbamates with various cyclic anhydrides,12 or of
c
-amino butyrate hydrochloride with isatoic anhydride13 in pres-
ence of DMAP as catalyst. Recently, direct metalation of heteroar-
omatic esters and nitriles using mixed lithium–cadmium base
followed by trapping with iodine and subsequent Buchwald–
N
O
N
O
N
N
H
H
N
N
Rutaecarpine (1)
Evodiamine (2)
⇑
Corresponding author. Tel.:+91 33 2473 3491; fax: +91 33 2473 5197.
E-mail address: nirup@iicb.res.in (N.B. Mondal).
Figure 1.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.019

3034
A. Maity et al. / Tetrahedron Letters 52 (2011) 3033–3037
R
R
R1
R
R
DMF
850C, 6h
CuI in DMF
+
N
N
N
NH
Cs2CO3, L-proline
85oC, 6 h
N
NH2
Br
N
NH2
Br
Br
Br Br
R1
R1
4a-b
3a-e
[O]
6a-h
7a-h
R1
5a-h
a; R=R1=H
b; R=5-Me, R1=H
c; R=4-Me, R1=H
R
a; R1=H
b; R1=4-OMe
d; R=H,
R1=4-OMe
a; R=H
e; R=Br, R1=4-OMe
f; R=5-Me, R1=4-OMe
g; R=4-Me, R1=4-OMe
b; R=5-Br
c; R=5-Me
d; R=4-Me
e; R=5-I
N
N
O
h; R=I,
R1=4-OMe
R1
8a-h
R
R
R
R
Br
CuI in DMF
DMF
850C, 6h
N
N
N
NH
+
Cs2CO3, L-proline
85oC, 6 h
Br
N
NH2
N
NH2
Br
Br
Br
[O]
11a-e
12a-e
3a-e
a; R=H
b; R=5-Br
c; R=5-Me
d; R=4-Me
e; R=5-I
9
R
10a-e
N
N
O
13a-e
Scheme 1. Synthesis of pyrido[2,1-b]quinazolin-11-ones (8a–h) and benzo[h] pyrido[2,1-b] quinazolin-7-ones (13a–e).
(1.5 equiv) in the same pot and heating continued at 85 °C (Scheme
1). The reaction was completed within another 12 h and afforded
the product 8a. The product was isolated in 26% yield and charac-
terized as pyrido[2,1-b]quinazolin-11-one from spectral analysis
(1H, 13C NMR and mass spectroscopy).
In order to improve the yield of 8a, we performed the reactions
using different types of bases viz. sodium carbonate, sodium or
potassium acetate, cesium carbonate; basic alumina, and amberlite
IRA-402(OH) ion exchange resin (Table 1, entries 1–8). Cesium car-
bonate appeared to be the most effective and the yield increased to
40%. For further improvement of the yield we used different types
ment in yield could indeed be observed in all the cases in shorter
period of time but -proline emerged as the most effective one pro-
ducing the highest yield (entry 9) of the product. It is noteworthy
that when reactions were performed in absence of CuI or ligand,
the formation of the product was also observed, but the yield
was only about 10%.
L
We next explored the scope of this reaction using other sub-
strates and reagents and the operations occurred quite smoothly
furnishing the products (Scheme 1) in good to very good yields.
The methodology was also extended to 1-amino isoquinoline
(14) to obtain some novel tetracyclic and pentacyclic quinazoli-
none scaffolds (Scheme 2, Table 2). All the compounds were char-
acterized by detailed spectroscopic analysis (1H, 13C, mass).
However, when the reaction was tried with 2-amino-6-picoline
as substrate, no pyridinium salt was obtained. This might be due
to the steric hindrance of the 6-methyl group in the formation of
the salt. Begouin et al.17 had described quite similar results in case
of intramolecular cyclization of pyridine nitrogen with carboxylate
group.
It is notable that in the earlier procedures the first step con-
sisted of a Buchwald–Hartwig15 or Ullman condensation18 or sim-
ple nucleophilic aromatic substitution19 involving the amine and
the halogen; this was followed by intramolecular cyclization be-
tween the pyridine or isoquinoline nitrogen and the ester or acid
carbonyl under heating15,18 or ultrasound19 to form the quinazoli-
none. In the present case, the first step produced the pyridinium
salt of bromo benzyl bromide (5a), which thereafter underwent
metal catalyzed intramolecular coupling reaction to form the qui-
nazolium salt (6a) and subsequent aerial oxidation at the benzylic
position to form the quinazolinone moiety (8a). We were also able
to isolate the pyridinium salt of bromo benzyl bromide (5a), and
quinazolinium salt (6a) which was used successfully to the subse-
quent steps to support the plausible mechanistic pathway of the
of bi-dentate ligand viz. L-proline, pipecolinic acid, ethylene dia-
mine, or sarcosine (entries 9–13). Gratifyingly, a marked improve-
Table 1
Synthesis of quinazolinones using various bases and ligands
Entrya
Base
Ligands
Time (h)
Yieldb (%)
1.
2.
3.
4.
5.
6.
7.
8.
9.
Na2CO3
K2CO3
NaOAc
KOAc
Basic alumina
Amberlite 402(OH)
K3PO4
Cs2CO3
Cs2CO3
—
—
—
—
—
—
—
—
12
12
12
12
12
12
12
12
6
22
26
20
25
20
28
30
40
90
L
-Proline
10.
Cs2CO3
12
90
L-Proline
11.
12.
13.
Cs2CO3
Cs2CO3
Cs2CO3
Picolinic acid
Ethylene diamine
Sarcosine
6
6
6
71
60
58
a
All the reaction was performed with 2-aminopyridine (1 mmol), 2-bromoben-
zyl bromide (1 mmol) using CuI at 85 °C in DMF.
b
Yield refers to pure products after crystallization.

A. Maity et al. / Tetrahedron Letters 52 (2011) 3033–3037
3035
R1
CuI in DMF
DMF
N
N
N
NH
CS2CO3,L-proline
85oC, 6h
850C, 6h
N
NH2
Br
Br
+
Br
Br Br
N
NH2
R1
R1
[O]
4a-b
17a-b
16a-b
R1
15a-b
14
N
N
O
R1
18a-b
CuI in DMF
CS2CO3,L-proline
N
N
N
NH
Br
DMF
+
Br
N
NH2
Br
85oC, 6h
850C, 6h
N
NH2
Br
Br
[O]
21
20
9
14
19
N
N
O
22
Scheme 2. Synthesis of isoquino[1,2-b]quinazoline-8-one and 6a, 14-diaza-dibenzo [a j] anthracen-7-one.
Table 2
Construction of pyrido[2,1-b]quinazolin-11-ones (8a–h), benzo[h] pyrido[2,1-b] quinazolin-7-ones (13a–e), isoquinolino[1,2-b]quinazolin-8-ones (18a–b) and 6a, 14-diaza-
dibenzo[a, j] anthracen-7-one (22)
Entry
Substrate
Bromobenzyl/naphthyl bromide
Producta
Timeb (h)
Yieldc (%)
O
1.
3a
4a
N
8a
8b
6
90
N
O
CH3
2.
3.
3c
4a
4a
6
6
86
85
N
N
N
O
3d
8c
N
CH3
O
MeO
MeO
4.
5.
3a
3b
4b
4b
8d
8e
6
6
84
81
N
N
O
Br
N
N
(continued on next page)

3036
A. Maity et al. / Tetrahedron Letters 52 (2011) 3033–3037
Table 2 (continued)
Entry
Substrate
Bromobenzyl/naphthyl bromide
Producta
Timeb (h)
Yieldc (%)
86
O
MeO
MeO
CH3
6.
7.
8.
3c
4b
4b
4b
8f
6
N
N
O
N
N
3d
3e
8g
8h
6
6
83
80
N
O
CH3
I
MeO
N
O
N
9.
3a
3b
3c
3d
3e
14
14
14
9
13a20
13b
13c
13d
13e
18a
18b
22
6
6
6
6
6
6
6
6
90
83
87
87
80
91
89
87
N
O
Br
N
N
N
N
10.
11.
12.
13.
14.
15.
9
N
O
CH3
9
N
O
9
N
O
CH3
I
9
N
N
O
N
4a
4b
9
O
MeO
N
N
O
N
N
16.
a
All the products were characterized by 1H, 13C NMR and Mass spectroscopy.
After formation of the salt the reaction required another 6 h for completion of the desired product.
Yield refers to pure products after crystallization.
b
c
reaction as depicted in Scheme 1. Both the products 5a, and 6a
were confirmed by spectral analysis (given in Supplementary
data).We also assumed that the formation of other compounds
(8b–h, 13a–e, 18a–b, and 22) too followed the same mechanistic
path way.
In conclusion, we have developed a simple, convenient, and effi-
cient one step methodology for the construction of linearly/angu-
larly fused novel tri, tetra and pentacyclic quinazolinones
using cheap and easily available reagents. The notable features
are moderate reaction conditions, greater selectivity, and opera-
21

A. Maity et al. / Tetrahedron Letters 52 (2011) 3033–3037
3037
A.; Paira, P.; Saha, P.; Naskar, S.; Paira, R.; Banerjee, S.; Sahu, N. P.; Mondal, N.
B.; Luger, P.; Weber, M. Tetrahedron 2009, 65, 6941–6949.
17. Begouin, A.; Hesse, S.; Queiroz, M. J. R. P.; Kirsch, G. Synthesis 2006, 2794–
2798.
tional simplicity that make it an attractive and useful process for
the synthesis of newer heteroaromatics of biological importance.
18. Pellón, R. F.; Docampo, M. L.; Kunakbaeva, Z.; Gómez, V.; Castro, H. V. Synth.
Commun. 2006, 36, 481–485.
Acknowledgments
19. Palacios, M. L. D.; Comdom, R. F. P. Synth. Commun. 2003, 33, 1777–
1781.
20. Hesse, S.; Kirsch, G. Synthesis 2007, 1571–1575.
21. General reaction procedure for the synthesis of linear and angular fused
quinazolinones:
We are thankful to the Director, IICB for laboratory facilities,
and the Council of Scientific and Industrial Research (CSIR) for fel-
lowships to S.M., R.P., A.H., S.N., K.B.S., P.S. and DBT for fellowships
to A.M. We are also thankful to Dr. B. Achari, Emeritus Scientist,
CSIR, for his valuable suggestions.
One mmol each of the 2-aminopyridine [or 2-aminoisoquinoline] (3a–e or 14)
derivatives and 1- bromo-2-bromomethyl benzene [or 1-bromo-2-
bromomethyl-naphthalene] (4a–b or 9) derivatives were dissolved in dry
DMF and heated at 85 °C for almost 6 h in a 100 ml RB flask. Then 1.5 equiv of
Cs2CO3, 10 mol % of CuI and 20 mol % L-proline were added to the solution and
Supplementary data
heated with constant stirring for 6 h at 80–85 °C. After completion of the
reaction (monitored by TLC), the contents were cooled to room temperature.
Then water was added to the mixture, the content was transferred to a
separating funnel and extracted with ethyl acetate. The organic layer was
washed thoroughly with water until free from alkali, dried over anhydrous
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.04.019.
sodium sulfate, and evaporated to dryness in
a rotary evaporator under
reduced pressure. The residue was chromatographed over silica gel (60–
120 mesh), eluting with a mixture of hexane and ethyl acetate in different
ratios.
(a) Spectral data of compound 8a: Yellowish product; Rf = 0.59 (20% EtOAc–Pet
ether); mp: 210–212 °C; 1H NMR (300 MHz, CDCl3) d 6.88 (m, 1H), 7.50 (m,
3H), 7.83 (m, 2H), 8.46 (d, 1H, J = 8.1 Hz), 8.89 (d, 1H, J = 7.2 Hz); 13C NMR
(75 MHz, CDCl3) d 112.4 (CH), 116.2 (C), 125.1 (CH), 126.2 (CH), 126.6 (CH),
126.8 (CH), 127.2 (CH), 134.0 (CH), 135.0 (CH), 147.6 (C), 148.4 (C), 158.9 (CO);
MS [ESI] m/z: 197 [M+H]+; HRMS (ESI) m/z: calcd for C12H8N2ONa: [M+Na]+;
219.0529 found; 219.0521.
(b) Spectral data of compound 13a: Yellowish product; Rf = 0.97 (20% EtOAc–Pet
ether); mp: 198–199 °C (lit20 mp 195 °C); 1H NMR (600 MHz, CDCl3) d 7.01 (m,
1H), 7.63 (m, 1H), 7.71(d, 1H, J = 7.2 Hz), 7.74 (m, 2H), 7.78 (d, 1H, J = 9.0 Hz),
7.92 (d, 1H, J = 7.8 Hz), 8.32 (d, 1H, J = 8.4 Hz), 9.04 (d, 1H, J = 7.2 Hz), 9.20 (d,
1H, J = 7.8 Hz); 13C NMR (150 MHz, CDCl3) d 112.1 (C), 113.5 (CH), 122.4 (CH),
125.4 (CH), 125.7 (CH), 126.8 (CH), 126.9 (2 Â CH), 127.9 (CH), 129.7 (CH),
129.8 (C), 134.2 (CH), 136.4 (C), 147.6 (C), 148.0 (C), 158.6 (CO); MS [ESI] m/
z:247 [M+H]+, 269 [M+Na]+; HRMS (ESI) m/z: calcd for C16H11N2O: [M+H]+
247.0866; found; 247.0861.
References and notes
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ether); mp: 293–294 °C, 1H NMR (300 MHz, CDCl3) d 7.14 (d, 1H, J = 7.8 Hz),
7.71 (m, 3H), 7.80 (d, 2H, J = 8.7 Hz), 7.91 (m, 2H), 8.32 (d, 1H, J = 8.7 Hz), 8.77
(d, 1H, J = 7.8 Hz), 9.31 (m, 2H); 13C NMR (75 MHz, CDCl3) d 113.6 (C), 113.8
(CH), 121.9 (CH), 122.4 (CH), 125.4 (CH), 126.0 (CH), 126.4 (CH), 126.7 (CH),
127.2 (CH), 127.6 (C), 127.8 (CH), 128.4 (CH), 129.4 (CH), 130.0 (C) 132.1 (CH),
132.9 (C), 136.3 (C), 145.9 (C), 146.3 (C), 159.1 (CO); MS [ESI] m/z:297 [M+H]+,
319 [M+Na]+, HRMS (ESI) m/z: calcd for C20H12N2ONa: [M+Na]+ 319.0842;
found: 319.0888.
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(d) Spectral data of compound 6a: 1H NMR (600 MHz, DMSO-d6) d 3.34 (s, 2H,
CH2), 5.71 (m, 1H), 6.22 (s, 1H), 6.38 (d, 1H, J = 9.0 Hz), 6.82 (m, 1H), 6.87 (dd,
1H, J = 1.2, 7.8 Hz), 7.22 (m, 2H), 7.33 (m, 1H), 7.64 (dd, 1H, J = 1.2, 7.8 Hz, NH);
13C NMR (150 MHz, DMSO-d6) d 52.2 (CH2), 101.7 (CH), 120.9 (CH), 122.3 (C),
127.6 (CH), 127.8 (CH), 128.8 (CH), 132.5 (CH), 133.7 (CH), 136.4 (C), 138.3
(CH), 158.3 (C).
16. (a) Paira, P.; Hazra, A.; Sahu, K. B.; Banerjee, S.; Mondal, N. B.; Sahu, N. P.;
Weber, M.; Lugar, P. Tetrahedron 2008, 64, 4026–4036; (b) Sahu, K. B.; Hazra,