A simple one pot synthesis of novel tricyclic quinazolinones

Article abstract of DOI:10.1016/j.tetlet.2017.01.106

Synthesis of a series of tricyclic quinazolinones have been accomplished starting from anthranilamide and 1,3-cyclic dione promoted by TsOH·H₂O The protocol presented herein based on retro-Dieckmann type reaction, leading to incorporation of dione as an acyclic unit into the product. Simple reaction conditions, broad scope, excellent yields are the advantages of this protocol. Further, this methodology is extended to the synthesis of pyridopyrimidinones and benzimidazopyridines.

Full text of DOI:10.1016/j.tetlet.2017.01.106

Accepted Manuscript
A simple one pot synthesis of novel tricyclic quinazolinones
Chiranjeevi Bingi, Kaushik Yadav Kola, Ashok Kale, Jagadeesh Babu
Nanubolu, Krishnaiah Atmakur
PII:
S0040-4039(17)30150-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.01.106
TETL 48609
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
2 January 2017
28 January 2017
31 January 2017
Please cite this article as: Bingi, C., Kola, K.Y., Kale, A., Nanubolu, J.B., Atmakur, K., A simple one pot synthesis
of novel tricyclic quinazolinones, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.01.106
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Graphical Abstract
A simple one pot synthesis of novel tricyclic
quinazolinones
Leave this area blank for abstract info.
Chiranjeevi Bingi,a Kaushik Yadav Kola,a Ashok Kale,a Jagadeesh Babu Nanubolub and Krishnaiah Atmakur*ac

1
Tetrahedron Letters
A simple one pot synthesis of novel tricyclic quinazolinones
Chiranjeevi Bingi,a Kaushik Yadav Kola,a Ashok Kale,a Jagadeesh Babu Nanubolub and Krishnaiah
Atmakur*ac
a Division of Crop Protection Chemicals, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India.
b Laboratory of X-ray crystallography, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India.
cAcSIR- Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Synthesis of a series of tricyclic quinazolinones have been accomplished starting from
anthranilamide and 1,3-cyclic dione promoted by TsOH.H2O. The protocol presented herein
based on retro-Dieckmann type reaction, leading to incorporation of dione as an acyclic unit into
the product. Simple reaction conditions, broad scope, excellent yields are the advantages of this
protocol. Further, this methodology is extended to the synthesis of pyridopyrimidinones and
benzimidazopyridines.
Available online
Keywords:
2-amino benzamides
1,3-diketones
Quinazolinones
pyridopyrimidinones
benzimidazopyridines
Quinazolinones are an important class of compounds among
N-heterocycles owing to their diverse range of biological
However, they were unsuccessful to convert the
dihydroquinazolinones into tricyclic quinazolinones. Similarly,
Xiang-Shan Wang14 reported the iodine-catalyzed reaction of 2-
aminobenzamides with 1,3-cyclohexanediones to give
quinazolin-4(3H)-one and bis quinazolin-4-(3H)-one derivatives.
properties
such
as
anticancer,1
antiinflammation,2
antihypertensive,3 antitumor4 and antibacterial activity.5 Some of
these compounds were also reported as potent chemotherapeutic
agents in the treatment of tuberculosis.6 Well-known
indoloquinazoline alkaloid i.e. Rutaecarpine and its 7,8-dehydro
analogue7 is known to exhibit anti-inflammatory activity. Further,
2,3-tetramethylene-4-(3H)-quinazolinone
isolated from mackinalaya species has been reported for
bronchodilatory, anti-inflammatory, antimicrobial and
(mackinazolinone)8
antidepressant activities. Out of these quinazolinone moieties,
4(3H)-quinazolinones are most prevalent either as intermediates
or as natural products in many biosynthetic pathways. Based on
the importance of these chemical entities, a great deal of effort
has been devoted to the synthesis of these compounds and thus a
number of protocols have appeared. For example, diverse N-
fused heterocycles have been synthesized from pyridine
derivatives
via
transition-metal
catalyzed
coupling,
cycloisomerization, oxidation, and other reactions.9 Recently, Yu
zhou reported the synthesis of pyrido / pyrrolo[2,1-b]quinazolin-
9(1H)-ones
through
silver
mediated
intramolecular
hydroamination reaction.10
Figure-1: Selected structures of fused quinazolinones.
Beller, Wu reported the synthesis of fused quinazolinones by
palladium-catalyzed carbonylation
/ nucleophilic aromatic
substitution sequence.11 11H-Pyrido[2,1-b]quinazolin-11-one was
prepared by the palladium-catalyzed C−H carbonylation of N-
aryl-2-aminopyridines.12 In 1983, K. Sumoto and co-workers
However, to the best of our knowledge, there are no reports
available on the synthesis of tricyclic quinazolinones by
incorporating 1,3-dione as an acyclic unit. With this background
and also as a part of our ongoing research interest on the
synthesis of N-heterocyclic new chemical entities of biological
interest,15 we have come out with a simple, so far unreported
reported
the
synthesis
of
2-substituted
4-oxo-3,4
dihydroquinazolines and 1-methyl-3,4-dihydropyrido[1,2-a]
benzimidazoles by fusing enamino-ketones at 250-260 oC.13

2
Tetrahedron Letters
On the other hand, the same reaction when conducted
methodology for synthesis of tricyclic quinazolinones in a one
independently in presence of CSA and SnCl2.2H2O in xylene in a
sealed tube, gave compound 4a exclusively (table-1, entries
7&9), whereas in presence of BSA formation of 3a and 4a were
observed in lower yields. Further, no reaction was observed with
trifluoroacetic acid and also with the sulphuric acid. Having
obtained the composite results from the aforesaid studies, it was
decided to scrutinize the TsOH.H2O quantity and streamline the
reaction parameters to obtain 4a.
pot two component reaction where 1,3-dione incorporates as an
acyclic unit into the product.
Initially, we have conducted a reaction with anthranilamide
o
(1a) and dimedone (2a) by employing TsOH.H2O at 150 C
under neat reaction condition. Interestingly, formation of 3a and
4a were observed in poor yields. In order to obtain the compound
4a exclusively, the same reaction was carried out by employing
benzenesulfonic acid, camphorsulfonic acid and SnCl2.2H2O
independently in toluene medium at 150 oC temperature in sealed
tube but ended up with the same mixture of 3a and 4a.
Nevertheless, yield of 4a improved to around 55% (table-1).
In this instance, a reaction was carried out with 1a and dimedone
by employing 50 mole% TsOH.H2O in xylene and obtained the
product 4a in 86%yields (table-1, entry-15). However, the same
reaction when conducted with 40 mole% TsOH.H2O, decreased
in yield i.e., 79% was observed (table-1, entry-16). Further, there
was no perceptible improvement in the yields when dosage of
TsOH.H2O increased. Therefore, it was concluded that 50 mole%
Table 1. Optimization of reaction conditions to obtain
tricyclic quinazolone compound (4a).a
o
of TsOH.H2O in Xylene at 150 C was found to be a suitable
parameter to obtain tricyclic quinazolinones (4). Dosage of
TsOH.H2O was further substantiated by conducting the
controlled experiments with 25 mole% of TsOH.H2O and
obtained 3a in 55 % and tricyclic quinazolinone compound (4a)
only in 28 % yields (Scheme-1). Further, compound 3a was
exclusively treated with 25 mole% TsOH.H2O and was
completely converted to 4a. This is further evident that 50
mole% of TsOH.H2O is essential and at the same time it is
responsible for ring cleavage and as well as for ring closing.
S.
No
Solvent
Catalyst
Quan
tity
Time
Yield
(%)
3a
Yield
(%)
4a
1
Neat
TsOH.H2O
1eq
10h
40
35
2
3
Toluene
Toluene
TsOH.H2O
CSA
1eq
1eq
8h
8h
20
21
58
55
4
5
6
7
8
9
Toluene
Toluene
BSA
SnCl2.2H2O
TsOH.H2O
CSA
1eq
1eq
1eq
1eq
1eq
1eq
8h
8h
8h
8h
8h
8h
25
21
-
45
56
86
78
68
80
Scheme-1: Control Experiments
m-Xylene
m-Xylene
m-Xylene
m-Xylene
-
BSA
10
-
SnCl2.2H2O
10
11
12
13
m-Xylene
m-Xylene
m-Xylene
AcOH
FeCl3
CF3COOH
H2SO4
1eq
1eq
1eq
1eq
8h
8h
8h
8h
10
-
70
-
-
-
TsOH.H2O
40
25
Looking at the formation of 3a and 4a, we postulated a
pathway for the formation of these compounds where 1a reacts
with 2a leading to enamino ketone followed by the formation of
spiro compound. On subsequent ring cleavage of spiro compound
in retro-Dieckmann type reaction under acidic condition lead to
compound 3a.13 Next, lone pair electrons on the amide nitrogen
of 3a are attacking on the carbonyl carbon of acyclic unit leading
to the formation of tricyclic ring followed by subsequent
dehydration (Scheme-2) is resulting in to the product 4a.
14
15
Ethanol
m-Xylene
TsOH.H2O
TsOH.H2O
1eq
0.5 eq
8h
8h
65
-
-
86
16
17
m-Xylene
m-Xylene
TsOH.H2O
I2
0.4 eq
1eq
8h
8h
-
79
10
68
aReaction conditions: 2-amino benzamide (1a, 3.67 mmol), dimedone
(2a, 3.67 mmol), additive and solvent (5ml) were stirred in a sealed tube
at 150 oC temperature for 8h. Yields refer to pure products after column
chromatography.
Scheme-2: Plausible mechanism for formation of 4a
Next, the same reaction was further carried out in
xylene in presence of TsOH.H2O (1equivalent) under similar
reaction conditions in sealed tube. Interestingly, this time
compound 4a was obtained exclusively in 86%yields (table 1,
entry 6). Structure of 4a was characterized by the spectral data
and unambiguously confirmed by the X-ray crystallography
studies (Fig-2).16
With the set reaction conditions on hand, the scope of
this protocol was generalized by extending to various
anthranilamides bearing electronic donating and electron
withdrawing groups and also varying 1,3-diones leading to 4a-k.
To our satisfaction this method is highly compatible and no
electronic effect was observed. However, the yields were varied.
Compounds with electronic donating groups gave the better
yields when compared to the electron withdrawing groups
(scheme-3). Encouraged by the synthesis of tricyclic
Figure-2: ORTEP diagram of compound 4a

3
quinqzolinones (4a-g) exclusively in excellent yields, this
protocol is extended to prepare trifluoro methyl substituted
tricyclic quinqzolinones compounds (4h-k) in good yields.
Scheme-3: Preparation of tricyclic quinazolinones (4) from
anthranilamide and dimedone.a
a Reaction conditions: 1,2-diamino benzene (5, 4.62 mmol), cyclic 1,3-dione
(2, 4.57 mmol), TsOH.H2O (2.31 mmol) and m-xylene (5ml) were stirred in a
sealed tube at 150 oC temperature for 8h. Yields refer to pure products after
column chromatography.
Furthermore, this protocol is also extended to acyclic ketones,
where 2-amino benzamides, 2-amino nicotinamides are
successfully reacted with acyclic 1,3-diones leading to
quinazolones17 and pyridopyrimidinones (7). It is notable to
mention that products 7 were obtained in good yields with
20 mole% of TsOH.H2O (Scheme-5) in toluene medium.
Scheme-5: Preparation of quinazolin-4(3H)-one (7) from 2-
amino benzamides and 1,3-diketone.a
aReaction conditions: 2-amino benzamide (1, 3.67 mmol), cyclic 1,3-dione (2,
3.67 mmol), TsOH.H2O (1.83 mmol) and m-xylene (5ml) were stirred in a
o
sealed tube at 150 C temperature for 8h. Yields refer to pure products after
column chromatography.
____________________________________________________________________________________________________
Further, this protocol also extended to 1,2-diaminobenzene (5) to
result in corresponding tricyclic benzo imidazo pyridine
compounds (6) in high yields (Scheme-4).
aReaction conditions: 2-amino benzamide (1, 3.67 mmol), acetyl acetone
(4.04 mmol), TsOH.H2O (0.73 mmol) and toluene (5ml) b2-amino benzamide
(1, 3.67 mmol), TsOH.H2O (0.73 mmol) in 5 ml of DMF were stirred in a
o
sealed tube at 120 C temperature for 10h. Yields refer to pure products after
Scheme-4: Preparation of 3,4-dihydrobenzo[4,5]imidazo[1,2-
a]pyridines (6) from 1,2-diamino benzene and 1,3-diketone.a
column chromatography.
In conclusion we have developed a novel method for
the synthesis of tricyclic quinazolinones by incorporating
dimedone as a C6-acyclic unit which was derived from retro-
Dieckmann type ring cleavage. To the best of our knowledge this
is for the first time that the dione moiety is incorporated as an C6-
acyclic unit to get the tricyclic quinazolinones. Further, this
method has wide applicability, high compatibility and may useful
in synthesizing more N-containing heterocycles.
Acknowledgments
We are grateful to SERB-DST New Delhi for financial
support (grant no. SB / EMEQ-075 / 2013). BCJ is thankful to
UGC, New Delhi for SRF.

4
Tetrahedron Letters
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5
Highlights
A simple one pot synthesis of novel tricyclic quinazolinones
 TsOH.H2O induced synthesis of tricyclic quinazolinones from anthranilamide and diones
 Protocol based on retro-Dieckmann type reaction
 Incorporation of dione as an acyclic unit into the product stream for the first time
 Methodology extended to pyridopyrimidinones and benzimidazopyridines
 Simple reaction conditions, broad scope and excellent yields.