Metal–Catalyst-Free Green and efficient synthesis of five and six membered fused N-heterocyclic quinazoline derivatives

Article abstract of DOI:10.1016/j.tetlet.2016.09.094

An efficient and green approach has been developed for the construction of Tetracyclic nitrogen-bridgehead compounds were designed and synthesized in good yields. The reaction of easily prepared 3-bromoisobenzofuran-1(3H)-one with isatoic anhydride and amines gave the desired isoindoloquinazolinone derivatives in moderate to good yields. It is also amenable for scale-up.

Full text of DOI:10.1016/j.tetlet.2016.09.094

Accepted Manuscript
Metal-Catalyst-Free Green and efficient synthesis of five and six membered
fused N-heterocyclic quinazoline derivatives
M.V. Madhubabu, R. Shankar, G. Rajeshwar Reddy, T. Srinivasa Rao, Mandava
V. Basaveswara Rao, Ragunadh Akula
PII:
S0040-4039(16)31287-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.09.094
TETL 48164
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
15 August 2016
27 September 2016
28 September 2016
Please cite this article as: Madhubabu, M.V., Shankar, R., Rajeshwar Reddy, G., Srinivasa Rao, T., Basaveswara
Rao, M.V., Akula, R., Metal-Catalyst-Free Green and efficient synthesis of five and six membered fused N-
heterocyclic quinazoline derivatives, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.09.094
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Metal-Catalyst-Free Green and efficient synthesis of five and six membered fused N-heterocyclic
quinazoline derivatives.
M. V. Madhubabua, R. Shankara, G. rajeshwar Reddy a, T. Srinivasa Raoa, Mandava V. Basaveswara Rao*b and
Ragunadh Akula*a

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Tetrahedron Letters
Metal-Catalyst-Free Green and efficient synthesis of five and six membered fused N-heterocyclic
quinazoline derivatives.
M. V. Madhubabua, R. Shankara, G. Rajeshwar Reddy a, T. Srinivasa Rao a, Mandava V. Basaveswara Rao*b and
Ragunadh Akula*a
aTechnology Development Centre, Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Ltd, Hyderabad 500049, India,bDepartment of Chemistry,
Krishna university, Machilipatnam, Andhra Pradesh, India.
*E-mail: raghunadha@drreddys.com
ABSTRACT
An efficient and green approach has been developed for the construction of Tetracyclic nitrogen-
bridgehead compounds were designed and synthesized in good yields. The reaction of easily
prepared 3-bromoisobenzofuran-1(3H)-one with isatoic anhydride and amines gave the desired
Isoindoloquinazolinone derivatives in moderate to good yields. It is also amenable for scale-up.
Article history:
Received
Received in revised form
Accepted
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords: PEG, MCR
Water, Dihydroisoindolo[2,1-a]quinazoline-
5,11-dione
The controlled synthesis of different N-heterocycles is
essential in both the agrochemical and pharmaceutical
industries.1 Over the last few decades compounds
containing a quinazoline structure have been in the focus of
different research areas first due to their existence as a
common core structure in several drugs and natural
products.2 In addition many unnatural quinazolinones show
significant biological activities acting as anticancer,3
isatoic anhydride, an amine and 2-formyl benzoic acid,
11
using montmorillonite K10 as the catalyst. Bunce et al.
reported the synthesis of substituted quinazolinones using a
dissolving metal reduction–condensative cyclization
strategy 12 and Sashidhara team also reported the synthesis
of Dihydroisoindolo[2,1-a]quinazoline-5,11-dione by using
acetic acid.13 However, such syntheses are still suboptimal
because of the use of catalysts, forcing reaction conditions
and long reaction times. Methodologies often address the
growing concern about environmental safety and hazard.
Since performing chemical reactions in water in the
presence of a catalyst derived from biomass enhances the
greenness of the process, the development of such economic
and eco-friendly methodologies therefore is the central
focus in the area of green and sustainable chemistry. Our
group previously reported numerous protocols for the
synthesis of quinazolinone based biologically active natural
products and their derivatives.14 In this communication we
wish to report a Metal and Catalyst-Free Green and straight
antibacterial,4
anti-inflammatory,5
antihypertensive,6
antidiabetic,7 anticonvulsant,8 and antianxietic agents.9
Because of varied biological properties of quinazolinone
derivatives, it is essential to develop efficient and
convenient methods to prepare these derivatives.
Therefore, many groups used this nitrogen bridgehead core
structure as a vital component in the development of
numerous experimental therapeutics and prospective drug
candidates.10
Dihydroisoindolo[2,1-a]quinazoline-5,11-
dione is an important five and six membered fused N-
heterocyclic quinazoline derivative. Pal et al. synthesized
6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-dione
forward synthesis of dihydroisoindolo [2,1-a]quinazoline-
15
derivatives by employing a three component reaction of
5,11-dione
derivatives by using isatoic anhydride,16 an

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amine and 3-bromoisobenzofuran-1(3H)-one 17 in water and
PEG as a co solvent. The retro synthetic strategy employed
for the synthesis of dihydroisoindolo [2,1-a]quinazoline-
5,11-dione is depicted in Scheme 1.
H2O /PEG-400
(2:1)
H2O /PEG-400
(3:1)
20
23
24
95
95
95
12
12
12
86
88
92
H2O /PEG-400
(4:1)
[a] Isolated yield.
Reaction and conditions: Isatoic anhydride 1 (1.0 mmol),
propargyl amine 3 (1.1 mmol), 3-bromoisobenzo-furan-
1(3H)-one 2 (1.0 mmol), and water: PEG 400 (4:1) at 95 °C.
The solvents have a strong effect on these reactions with
respect to yield. The solvents namely Ethanol, 1,4-dioxane,
DMSO, DMF, PEG-400, PEG-200, Ethylene Glycol and
Water (Table 1, entries 1-13) were screened. Further we
have screened various combinations of other solvents like
H2O/Ethanol (1:1), H2O /MeCN (1:1), H2O/ Ethylene
Glycol (1:1), H2O/PEG-400 (1:1), H2O /PEG-400 (2:1),
H2O /PEG-400 (3:1) and H2O /PEG-400 (4:1) Table 1,
entries 14-24). Combination of water and PEG-400 (4:1)
had proven to be the best condition for this reaction (Table
1, entry 24).
Scheme 1: Retrosynthesis of 11.
Initially when isatoic anhydride 1, amine 3 and 3-
bromoisobenzofuran-1(3H)-one 2 were treated under the
conditions applied for construction of dihydroisoindolo
quinazoline in water gives 46% of the desired product 4a.
The compound 4a was characterized by 1H NMR, 13C
NMR, HRMS and IR. Substituted dihydroisoindolo [2,1-
a]quinazoline-5,11-dione. In an effort to develop optimal
conditions, various solvents were studied for the preparation
of 4. Initially, isatoic anhydride 1, propargyl amine 3, 3-
bromoisobenzofuran-1(3H)-one 2, were chosen as model
substrates to optimize reaction conditions.
The recovery solvent was examined in the reaction of
isatoic anhydride 1, propargyl amine
3
and 3-
bromoisobenzofuran-1(3H)-one 2 at 95 °C. When the
reaction was completed, filter the product and the recovered
solvent was reused in place of fresh solvent for this reaction
and several times without significant loss of activity. It was
found that the activities of recovered solvent and fresh
solvent were almost same and it was not impacting the
reaction time and yield over four runs (Table 3, entries 1–5).
Table 1: Screening of solvents.
Yielda
(%)
Temp Time
S.No.
Solvent
°C
(h)
1
Ethanol
75
24
52
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1,4-dioxane
DMF
DMSO
PEG 400
PEG 400
PEG 400
PEG 400
PEG 200
90
90
90
25
65
75
95
90
95
25
80
95
85
80
24
24
24
24
24
24
12
24
24
24
24
18
18
24
45
35
38
0
52
58
72
63
62
0
Table 2: Recover and Recyclability of PEG: water (1:4)
mixture.
Yielda (%)
S.No.
Cycle
Time (h)
1
Fresh
12
92
2
3
4
5
1
2
3
4
12
12
12
12
92
91
91
91
Ethylene Glycol
H2O
H2O
H2O
46
68
74
51
[a] Isolated yield.
H2O/Ethanol (1:1)
H2O /MeCN (1:1)
H2O/ Ethylene
Glycol (1:1)
H2O/PEG-400
(1:1)
H2O /PEG-400
(1:1)
H2O /PEG-400
(1:1)
Reaction and conditions: Isatoic anhydride 1 (1.0 mmol),
propargyl amine 3 (1.1 mmol), 3-bromoisobenzo-furan-
1(3H)-one 2 (1.0 mmol), and water: PEG 400 (4:1) at 95 °C.
16
17
18
19
90
30
60
95
24
12
16
12
42
40
70
90
With the optimized conditions in hand, we explored the
applicability of our reaction. We employed a variety of
substituted amines and substituted isatoic anhydrides the
results are summarized in Table 3, good yields were

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observed when the reaction was conducted with aliphatic
amines when compared to the aromatic amines due to the
more reactivity of aliphatic amine and substitution on
isatoic anhydrides not having any impact on yield when
compared to the simple isatoic anhydrides
Table 3: Synthesis of various dihydroisoindolo [2,1-a]quinazoline-5,11-dione derivatives.
Isotoic
anhydride
S.No.
1
Amine
Product
Yield (%)a
91
(in water)
2
3
4
5
1a
1a
1a
1a
87
92
81
71

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4
6
7
1a
1a
88
68
8
1a
71
73
9
1a
1a
10
82
69
11
12
1a
1a
76

5
13
14
1a
1a
68
71
15
16
1a
1a
66
92
17
18
19
3a
3l
90
78
88
1b
3p
Reaction and conditions: Isatoic anhydride 1 (1.0 mmol), amine 3 (1.1 mmol), 3-bromoisobenzo-furan-1(3H)-one 2 (1.0 mmol),
and water: PEG 400 (4:1) at 95 °C.

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The Scheme 2 represents a plausible mechanism for the
three component reaction leading to the compound 4. The
nucleophilic attack of primary amine on carbonyl group of
then undergo subsequent cyclization will yield 10 and
further cyclization of intermediate 10 with carboxylic acid
will yield 4. Path B: nitrogen nucleophile of 5 can attack
on carbonyl group of 3-bromoisobenzofuran-1(3H)-one 2
will yield the 7. Intermediate 7 rearranges to give diamide
intermediate 9; This could then undergo the HBr elimination
to give aldehyde intermediate 12 and subsequent cyclization
of 12 would give the product 4,.
isatoic anhydride
1 followed by ring opening and
subsequent decarboxylation provided the compound 5. Path
A: Nitrogen nucleophile of 5 can readily displaces the
bromine of 3-bromoisobenzofuran-1(3H)-one 2 will yield
the 6 which on deprotanation provides emine 8. This could
Scheme 2: The proposed reaction mechanism for the formation of 4.
of the products in shorter reaction time, easy work-up, and
reusability of the solvent.
Conclusion:
In conclusion, we have developed a short and efficient,
Metal free, Catalyst-Free, greener approach for the
synthesis of dihydroisoindolo [2,1-a]quinazoline-5,11-dione
derivatives in Water. This synthetic approach involves
construction of two new rings via sequential C–N bond
formation. Prominent advantages of this method are broad
scope, operational simplicity, economic viability, good yield
Acknowledgments:
The authors would like to thank Dr. H. Rama Mohan and
the analytical group of CPS-DRL for spectral data.

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Syam Kumar, U. K.; Raghunadh, A. RSC Advances 2016, 6,
36599.
References:
1.
(a) Horton, D. A.; Bourne, G. T.; Smyth, M. L. Chem. Rev. 2003,
15. (a) Avalani, J. R.; Patel, D. S.; Raval, D. K.; J. Mole. Cata. 2013,
90, 70; (b) Reddy, G. R.; Reddy, T. R.; Chary, R. G.; Joseph, S.
C.; Mukherjee, S.; Pal, M. Tetrahedron Lett. 2013, 54, 6744.
16. Shvekhgeimer, M. G. A. Chemistry of Heterocyclic Compounds
2001, 37, 385.
103, 893; (b) Comprehensive Heterocyclic Chemistry III;
Katritzky, A. R.; Ramsden, C. A.; Scriven, E. F. V.; Taylor, R. J.
K.; Eds.; Elsevier: Oxford, UK, 2008.
2.
3.
(a) Lee, S. H.; Son, J.-K.; Jeong, B. S.; Jeong, T.-C.; Chang, H.
W.; Lee, E.-S.; Jahng, Y. Molecules 2008, 13, 272; (b) Mhaske,
S. B.; Argade, N. P. Tetrahedron 2006, 62, 9787.
17. (a) Kubota, Y.; Tatsuno, T. Chem. Pharm. Bull. 1971, 19,
1226e1233; (b) Desai, R. A.; Chaphekar, S. S.; Samant, S. D.
Indian J. Chem., Sect. B 1999, 38, 810e813; (c) Janin, Y. L.;
Decaudin, D.; Monneret, C.; Poupon, M.-F. Tetrahedron 2004,
60, 5481; (d) Wang, J.; Johnson, D. M. Polym. Prepr. (Am. Chem.
Soc., Div. Polym. Chem.) 2007, 48, 481; (e) Wang, J.; Johnson, D.
M. Polym. Int. 2009, 58, 1234; (f) Nandakumar, M.;
Sivasakthikumaran, R.; Mohanakrishnan, A. K. Eur. J.
Org.Chem. 2012, 3647, (g) Kondo, Y.; Asai, M.; Miura, T.;
Uchiyama, M.; Sakamoto, T. Org. Lett. 2001, 3, 13.
(a) Jiang, J. B.; Hesson, D.; Dusak, B.; Dexter, D.; Kang, G.;
Hamel, E. J. Med. Chem. 1990, 33, 1721. (b) Cao, S. L.; Feng, Y.
P.; Jiang, Y. Y.; Liu, S. Y.; Ding, G. Y.; Li, R. T. Bioorg. Med.
Chem. Lett. 2005, 15, 1915.
4.
5.
6.
(a) Pendergast, W.; Johnson, J. V.; Dickerson, S. H.; Dev, I. K.;
Duch, D. S.; Ferone, R.; Hall, W. R.; Humphreys, J.; Kelly, J.
M.; Wilson, D. C. J. Med. Chem. 1993, 36, 2279. (b) Kung, P. P.;
Casper, M. D.; Cook, K. L.; Wilson L. L.; Risen, L. M.; Vickers,
T. A.; Ranken, R.; Blyn, L. B.; Wyatt, J. R.; Cook, P. D. J. Med.
Chem. 1999, 42, 4705.
(a) Rorsch, F.; Buscato, E.; Deckmann, K.; Schneider, G.;
Zsilavecz, M. S.; Geisslinger, G.; Proschak, E.; Grosch, S. J. Med.
Chem. 2012, 55, 3792. (b) De Laszlo, S. E.; Quagliato, C. S.;
Greenlee, W. J.; Patchett, A. A.; Chang, R. S. L.; Lotti, V. J.;
Chen, T. B.; Scheck, S. A.; Faust, K. A. J. Med. Chem. 1993, 36,
3207.
Chern, J. W.; Tao, P. L.; Wang, K. C.; Gutcait, A.; Liu, S. W.;
Yen, M. H.; Chien, S. L.; Rong, J. K. J. Med. Chem. 1998, 41,
3128.
7.
8.
Malamas, M. S.; Millen, J. J. Med. Chem. 1991, 34, 1492.
Wolfe, J. F.; Rathman, T. L.; Sleevi, M. C.; Campbell, J. A.;
Greenwood, T. D. J. Med. Chem. 1990, 33, 161.
9.
Mustazza, C.; Borioni, A.; Sestili, I.; Sbraccia, M.; Rodomonte,
A.; Ferretti, R.; Giudice, M. R. D. Chem. Pharm. Bull. 2006, 54,
611
10. Zheng, Y.; Bian, M.; Deng, X.-Q.; Wang, S.-B.; Quan, Z.-S.
Arch. Pharm. Chem. Life Sci. 2013, 346, 119.
11. Kumar, K. S.; Kumar, P. M.; Kumar, K. A.; Sreenivasulu, M.;
Jafar, A. A.; Rambabu, D.; Krishna, G. R.; Reddy, C. M.;
Kapavarapu, R.; Kumar, K. S.; Priya, K. K.; Parsa, K. V. L.; Pal,
M. Chem. Commun. 2011, 5010.
12. Bunce, R. A.; Nammalwar, B. J. Heterocycl. Chem. 2011, 48, 991
13. Sashidhara K. V.; Palnati G. R.; Avula S. R.; Kumar A. Synlett
2012, 23, 611.
14. (a) Raghavendra R, K.; Ramamohan, M.; Raghunadh, A.; Suresh
Babu, M.; Praveen Kumar, S.; Kalita, D.; Laxminarayana, E.;
Prasad, B.; Pal. M. RSC Advances , 2015, 5, 61575. (b) Murthy,
N, V.; Nikumbh, S, P.; Praveen Kumar, S.; Vaikunta Rao, L.;
Raghunadh, A. Tetrahedron Lett, 2015, 56, 5767-5770. (c) Rao,
A. V. D.; Vykunteswararao, B. P.; Bhaskarkumar, T.; Nivrutti, R.
J.; Dipak, K.; Kumar, J. D. L.; Siddaiah, V.; Douglas, S. P.;
Raghunadh. A. Tetrahedron Lett. 2015, 56, 4714; (d) Madhubabu,
M. V.; Shankar, R.; Satish. S. More, Basaveswara Rao, M. V.;

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Highlights of the work
 An efficient and green approach for the synthesis of Tetracyclic nitrogen-bridgehead
compounds.
 Synthetic approach involves construction of two new rings via sequential C–N bond
formation.
 Recover and Recyclability of solvent was established.