Studies on novel synthetic methodologies, part XII: An efficient one-pot access to 6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-diones and 5-phenylisoindolo[2,1-a]quinazolin-11(6a H)-ones

Article abstract of DOI:10.1055/s-0032-1317761

A simple and efficient procedure for the construction of 6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-dione and 5-phenylisoindolo[2,1-a] quinazolin-11(6aH)-one derivatives in acetic acid under catalyst-free conditions is described. Attractive features of this methodology are its versatility, ready availability of starting materials and the efficiency in creating a complex core in a single operation. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317761

LETTER
▌105
lSettteur dies on Novel Synthetic Methodologies, Part XII: An Efficient One-Pot
Access to 6,6a-Dihydroisoindolo[2,1-a]quinazoline-5,11-diones and
5-Phenylisoindolo[2,1-a]quinazolin-11(6aH)-ones
Efficient One-Pot Access to Quinazoline-5,11-diones
Koneni V. Sashidhara,*a Gopala Reddy Palnati,a Ranga Prasad Dodda,a Srinivasa Rao Avula,a Priyanka Swamib
a
Medicinal and Process Chemistry Division, Central Drug Research Institute, CSIR-CDRI, Lucknow 226001, India
Fax +91(522)2623405; E-mail: sashidhar123@gmail.com; E-mail: kv_sashidhara@cdri.res.in
b
Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli 229010, India
Received: 26.10.2012; Accepted after revision: 15.11.2012
Hybrid molecules that combine two heterocyclic structur-
al units of different nature generally lend themselves well
to rational drug design and often possess improved bio-
logical activities.15 A number of biologically potent hy-
Abstract: A simple and efficient procedure for the construction of
6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-dione and 5-phenyl-
isoindolo[2,1-a]quinazolin-11(6aH)-one derivatives in acetic acid
under catalyst-free conditions is described. Attractive features of
this methodology are its versatility, ready availability of starting brids have been described in the literature such as steroid
antibiotics,16 steroid nucleosides,17 triterpenoid pep-
materials and the efficiency in creating a complex core in a single
operation.
tides,18 and DNA-cleaving-agent amino acids.19 Multi-
Key words: one-pot synthesis, catalyst-free, 6,6a-dihydroiso-
indolo[2,1-a]quinazoline-5,11-dione, 5-phenylisoindolo[2,1-a]quin-
azolin-11(6aH)-one, 2-formyl benzoic acid
component reactions (MCRs), have proven to be one of
the most powerful methods to access complex structures
in a single synthetic operation from simple building
blocks20 and are very useful in the construction of diverse
chemical libraries of ‘drug-like’ molecules.21,22 Recently,
Pal et al. synthesized 6,6a-dihydroisoindolo[2,1-a]quin-
azoline-5,11-dione derivatives 8 by employing a three-
component reaction of isatoic anhydride, an amine and 2-
formylbenzoic acid, using montmorillonite K10 as the
catalyst.23a Additionally, Bunce et al. reported the synthe-
sis of substituted quinazolinones using a dissolving metal
reduction–condensative cyclization strategy.23b However,
such syntheses are still suboptimal because of use of cat-
alysts, forcing reaction conditions and long reaction
times.
Quinazolines, quinazolinones and isoindolinone, repre-
sent common structural units in many natural alkaloids in-
cluding rutaecarpine (1). They also show a range of
biological activities.1.In addition many unnatural quinaz-
olinones show significant biological activities acting as
anticancer,2 antibacterial,3 anti-inflammatory,4 antihyper-
tensive,5 antidiabetic,6 anticonvulsant,7 and antianxietic
agents.8 Figure 1 shows the chemical structures of some
potent biologically important quinazolinone, isoindolin-
1-one-based compounds and the general structure of our
synthesized prototype. The kinesin spindle protein inhibi-
tor 29 displays antimitotic activity and is in phase II clini-
cal trials, while methaqualone (3) is a clinically used
sedative.10 Furthermore, diproqualone 4 is used primarily
for the treatment of inflammatory pain associated with
osteoarthritis,11 while compound 5 possesses potent nico-
tinic acid receptor agonist activity for the treatment of
dyslipidemia.12 The isoindolinone (phthalimidine) motif
occurs as a core structure not only in several natural prod-
ucts such as lennoxamine (6)13 but also in a number of
pharmacologically relevant synthetic molecules, such as
pagoclone (7).14
As a part of our ongoing studies devoted towards the de-
velopment of a practical synthesis of biologically interest-
ing heterocyclic molecules,24 we have explored the
possibility of an operatively simple, catalyst-free synthe-
sis of 6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-di-
one derivatives. In the initial phase of this study we
investigated the cyclization reaction of 2-formylbenzoic
acid (3) with isatoic anhydride (1) and p-toluidine (2i) in
the absence of catalyst in ethanol under heating (Scheme
1) for two hours which yielded the required compound 4i
in 45% yield (Table 1, entry 1). Further optimization re-
O
N
NH2
O
+
+
O
COOH
N
N
O
CHO
H
O
1
2i
3
4i
Scheme 1 Reaction of isatoic anhydride (1), p-toluidine (2i) and 2-formylbenzoic acid (3)
SYNLETT 2013, 24, 0105–0113
Advanced online publication: 11.12.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317761; Art ID: ST-2012-D0922-L
© Georg Thieme Verlag Stuttgart · New York

106
K. V. Sashidhara et al.
LETTER
O
N
N
O
N
O
N
N
N
Br
HN
N
methaqualone (3)10
rutaecarpine (1)1
O
NMe
29
OMe
O
MeO
O
O
N
N
O
N
F
OH
OH
N
doproqualone (4)11
N
F
H
O
512
O
O
lennoxamine (6)13
O
R
O
N
N
N
N
Cl
N
O
our prototype (8)
O
pagoclone (7)14
Figure 1 Biologically active quinazolinone, isoindolinone-based compounds 1–7 and our prototype 8
sults are presented in Table 1. Replacement of ethanol
with acetic acid caused a sharp increase in the yield of this
reaction (85%; Table 1, entry 6). The solvent was found to
have a dramatic impact on the efficiency of the reaction
(Table 1, entries 9–13). On the other hand, the use of
CF3COOH completely closed down the reaction (Table 1,
entry 8). The cyclization ability of various binary solvent
systems such as ethanol–acetic acid (Table 1, entry 9),
acetonitrile–acetic acid (Table 1, entry 10) and DMF–
acetic acid (Table 1, entry 11) was also tried without suc-
cess.
Table 1 Effect of Reaction Conditions on the Cyclization of Isatoic
Anhydride (1), p-Toluidine (2i) and 2-Formylbenzoic Acid (3)
Entry Solvent
Temp (°C) Time (h) Yield (%)a
1
2
EtOH
90
90
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.0
0.75
2.0
45
35
30
30
40
85
40
–
i-PrOH
3
DMF
110
110
90
4
DMSO
5
MeCN
We also carried out the reaction in the absence of acetic
acid to confirm the cyclization ability of acetic acid. Thus,
among the solvents screened, only the acetic acid promot-
ed effective cyclization in high yield and short reaction
time (Table 1, entry 13). Further increases in the reaction
time did not increase the yield of the reaction (Table 1,
entries 6 and 12).
6
AcOH
110
110
110
100
100
110
110
110
90
7
1,4-dioxane
CF3COOH
AcOH–EtOH (7:3)
AcOH–MeCN (7:3)
AcOH–DMF (7:3)
AcOH
8
9
70
73
70
85
85
10
10
11
12
13
14
The scope of this one-pot three-component synthesis of
6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-dione de-
rivatives was next investigated. To explore the applicabil-
ity of our reaction, we employed a variety of substituted
aliphatic and aromatic amine derivatives in the reaction.
Though the reaction worked well in all cases, the yields
were better for the more nucleophilic aliphatic amines
than aromatic amines (Table 2).
AcOH
AcONa
a Yields after recrystallization from chloroform–hexane (2:8).
Synlett 2013, 24, 105–113
© Georg Thieme Verlag Stuttgart · New York

LETTER
Efficient One-Pot Access to Quinazoline-5,11-diones
107
1
All the synthesized25 compounds were confirmed by H of the product. The best results were obtained in acetic
NMR, 13C NMR, IR spectroscopy and mass spectrometry acid (pKa 4.76; Table 1, entries 6, 12 and 13), while the re-
and their comparison with published data in the case of action when performed in trifluoroacetic acid (pKa 0.23;
known compounds (4a–e,h,m,n).23
Table 1, entry 8) did not give any products, possibly be-
cause trifluoroacetic acid used in large excess as solvent,
is too strong an acid. These initial results indicate the im-
portant role of acetic acid as a solvent with optimum pKa
and, in some way, as an activator of the cyclization pro-
cess.
A plausible mechanism for the formation of 6,6a-di-
hydroisoindolo[2,1-a]quinazoline-5,11-diones is depicted
in Scheme 2.23a In order to elucidate the possible role of
acetic acid the reaction was performed at two different
pKa values. The reaction with sodium acetate (a weak
base) in ethanol (Table 1, entry 14) resulted in low yield
O
NH2
N
H
H
N
O
– CO2
AcOH
HO
NH
O
N
O
H
NH2
O
O
CHO
COOH
O
N
N
NH
O
H
O
HN
N
COOH
HO
N
COOH
O
– H2O
O
N
N
O
4c
Scheme 2 Plausible mechanism for the formation of 6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-diones derivatives
Table 2 General Synthesis of 6,6a-Dihydroisoindolo[2,1-a]quinazoline-5,11-diones Derivatives from Suitable Precursors
O
O
R
N
AcOH
NH2
O
+
+
R
COOH
N
110 °C
45–60 min
2a–q
N
O
CHO
H
O
1
3
4a–q
Entry
Amine 2
Product 4
Time (min)
Yield (%)a
O
NH
NH4OAc
2a
1
45
92
N
O
4a
© Georg Thieme Verlag Stuttgart · New York
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108
K. V. Sashidhara et al.
LETTER
Table 2 General Synthesis of 6,6a-Dihydroisoindolo[2,1-a]quinazoline-5,11-diones Derivatives from Suitable Precursors (continued)
O
O
R
N
AcOH
NH2
O
+
+
R
COOH
N
110 °C
45–60 min
2a–q
N
O
CHO
H
O
1
3
4a–q
Entry
Amine 2
Product 4
Time (min)
Yield (%)a
O
Me
N
MeNH2
2b
N
2
50
92
O
4b
O
N
N
NH2
3
4
45
48
91
90
2c
O
4c
O
N
N
NH2
2d
O
4d
OH
O
N
N
HO
NH2
5
50
92
2e
O
4e
O
N
OH
N
HO
NH2
6
50
90
2f
O
4f
O
O
N
O
OH
NH2
N
7
55
89
OH
2g
O
4g
Synlett 2013, 24, 105–113
© Georg Thieme Verlag Stuttgart · New York

LETTER
Efficient One-Pot Access to Quinazoline-5,11-diones
109
Table 2 General Synthesis of 6,6a-Dihydroisoindolo[2,1-a]quinazoline-5,11-diones Derivatives from Suitable Precursors (continued)
O
O
R
N
AcOH
NH2
O
+
+
R
COOH
N
110 °C
45–60 min
2a–q
N
O
CHO
H
O
1
3
4a–q
Entry
Amine 2
Product 4
Time (min)
Yield (%)a
O
NH2
N
8
48
80
N
O
2h
4h
O
NH2
N
N
9
45
85
O
..
2i
4i
Cl
NH2
O
N
a
10
50
80
N
O
Cl
2j
4j
OH
O
NH2
N
11
60
80
N
OH
O
..
2k
4k
O
NH2
NO2
N
12
60
82
N
NO2
O
2l
4l
© Georg Thieme Verlag Stuttgart · New York
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110
K. V. Sashidhara et al.
LETTER
Table 2 General Synthesis of 6,6a-Dihydroisoindolo[2,1-a]quinazoline-5,11-diones Derivatives from Suitable Precursors (continued)
O
O
R
N
AcOH
NH2
O
+
+
R
COOH
N
110 °C
45–60 min
2a–q
N
O
CHO
H
O
1
3
4a–q
Entry
13
Amine 2
Product 4
Time (min)
Yield (%)a
O
H2N
N
N
50
85
O
..
2m
4m
O
N
H2N
N
OMe
14
55
85
OMe
O
2n
4n
O
N
H2N
N
F
15
60
83
O
..
F
2o
4o
OMe
O
NH2
N
16
60
85
N
MeO
O
2p
4p
OMe
OMe
NH2
O
N
N
17
60
82
MeO
OMe
O
..
2q
4q
a Yields after recrystallization from chloroform–hexane (2:9).
The structural diversity of this reaction was further in- According to Table 3, in all the cases the reactions were
creased by using 2-aminobenzophenone (5b) instead of accomplished in relatively short reaction time and the
isatoic anhydride under similar reaction conditions, lead- products were obtained in good to excellent yields (more
ing to the formation of new 5-phenylisoindolo[2,1- than 70%). To determine the scope of this protocol, vari-
a]quinazolin-11(6aH)-one derivatives (Table 3, com- ous aliphatic and aromatic amine derivatives were
pounds 6a–e).
employed. However the reaction worked well with 2-amino-
Synlett 2013, 24, 105–113
© Georg Thieme Verlag Stuttgart · New York

LETTER
Efficient One-Pot Access to Quinazoline-5,11-diones
111
O
Cl
O
O
O
Cl
H
N
NH4OAc
+
+
OH
2
NH2
5b
3
COOH
A
NH
Cl
Cl
O
O
HO
NH
Cl
N
N
N
N
6b
COOH
B
C
Scheme 3 Plausible mechanism for the formation of 6b
benzophenone derivatives only. All compounds were In summary, we have developed an alternative, catalyst-
characterized through 1H NMR, 13C NMR, HRMS and IR free synthesis of 6,6a-dihydroisoindolo[2,1-a]quinazo-
spectroscopic studies26 (please refer to the Supporting In- line-5,11-diones and 5-phenylisoindolo[2,1-a]quinazolin-
formation).
11(6aH)-ones with excellent yields and short reaction
times. Attractive features of this methodology are its ver-
satility, the readily available starting materials needed,
and the efficiency in creating a complex core in a single
operation.
The proposed mechanism for the formation of the 5-phe-
nylisoindolo[2,1-a]quinazolin-11(6aH)-ones is shown in
Scheme 3.23a,27,28 The reaction is expected to proceed via
aldimine benzophenone intermediate A generated in situ
from the reaction of 5b with 2-formylbenzoic acid in ace-
tic acid. The reaction of intermediate A with ammonium
acetate results in the second intermediate imine B which
subsequently participates in an intramolecular cyclization
(C) followed by nucleophilic attack of the ring nitrogen
on the carbonyl of the carboxylic acid leading to the for-
mation of 6b.
Acknowledgment
The authors are grateful to the Director, CDRI, Lucknow, India for
constant encouragement, S.P. Singh for technical support, and SAIF
for NMR, IR, and mass spectral data. G.R.P, R.P.D and A.S.R are
thankful to CSIR, New Delhi, India for financial support. This is
CDRI communication number 8354.
Table 3 Three-Component Synthesis of 5-Phenylisoindolo[2,1-a]quinazolin-11(6aH)-one Derivatives 6a–e in One Pot
R3
R2
O
R2
R1
R1
CHO
N
AcOH
NH4OAc
+
+
110 °C, 0.75–1.0 h
N
NH2
R3
COOH
5a–e
O
6a–6e
Entry
R1
R2
R3
Time (min)
Product (yield, %)a
1
2
3
4
5
H
H
H
F
H
H
H
F
60
45
60
60
60
6a (75)
6b (80)
6c (75)
6d (80)
6e (70)
Cl
Cl
Cl
H
F
H
Br
a Yields are of the isolated product after purification by column chromatography.
© Georg Thieme Verlag Stuttgart · New York
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112
K. V. Sashidhara et al.
LETTER
(14) (a) Chen, M.; He, M.; Zhou, X.; Huang, L.; Ruan, Y.;
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
Huang, P. Tetrahedron 2005, 61, 1335. (b) Stuk, T. L.;
Assink, B. K.; Bates, R. C.; Erdman, D. T.; Fedij, V.;
Jennings, S. M.; Lassig, J. A.; Smith, R. J.; Smith, T. L. Org.
Process Res. Dev. 2003, 7, 851. (c) Favor, D. A.; Powers, J.
J.; White, A. D.; Fitzgerald, L. W.; Groppi, V.; Serpa, K. A.
Bioorg. Med. Chem. Lett. 2010, 20, 5666. (d) Shirasaka, T.;
Kunitake, T.; Tsuneyoshi, I. Brain Res. 2009, 1300, 105.
(e) Augner, D.; Gerbino, D. C.; Slavov, N.; Neudorfl, J. M.;
Schmalz, H. G. Org. Lett. 2011, 13, 5374.
m
iotSrat
ungIifoop
r
t
References and Notes
(1) For quinazolines in medicinal chemistry, see: (a) Foster, B.
A.; Coffrey, H. A.; Morin, M. J.; Rastinejad, F. Science
1999, 286, 2507. (b) Gundla, R.; Kazemi, R.; Sanam, R.;
Muttineni, R.; Sarma, J. A. R. P.; Dayam, R.; Neamati, N. J.
Med. Chem. 2008, 51, 3367. (c) Lüth, A.; Löwe, W. Eur. J.
Med. Chem. 2008, 43, 1478. (d) Lewerenz, A.; Hentschel,
S.; Vissiennon, Z.; Michael, S.; Nieber, K. Drug Dev. Res.
2003, 58, 420. (e) Doyle, L. A.; Ross, D. D. Oncogene 2003,
22, 7340. For quinazolinone, see: (f) Michael, J. P. Nat.
Prod. Rep. 2004, 21, 650. (g) Mhaske, S. B.; Argade, N. P.
Tetrahedron 2006, 62, 9787. For isoindolin-1-one, see:
(h) Moreau, A.; Couture, A.; Deniau, E.; Grandclaudon, P. J.
Org. Chem. 2004, 69, 4527. (i) Jagtap, P. G.; Southan, G. J.;
Baloglu, E.; Ram, S.; Mabley, J. G.; Marton, A.; Salzman,
A.; Szabó, C. Bioorg. Med. Chem. Lett. 2004, 14, 81.
(j) Cappelli, A.; Gallelli, A.; Braile, C.; Anzini, M.; Vomero,
S.; Mennuni, L.; Makovec, F.; Menziani, M. C.; De
Benedetti, P. G.; Donati, A.; Giorgi, G. Bioorg. Med. Chem.
2002, 10, 2681.
(2) (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.
(3) (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-
Lingardo, L.; Risen, L. M.; Vickers, T. A.; Ranken, R.; Blyn,
L. B.; Wyatt, J. R.; Cook, P. D. J. Med. Chem. 1999, 42,
4705.
(4) (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.
(5) 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.
(6) Malamas, M. S.; Millen, J. J. Med. Chem. 1991, 34, 1492.
(7) Wolfe, J. F.; Rathman, T. L.; Sleevi, M. C.; Campbell, J. A.;
Greenwood, T. D. J. Med. Chem. 1990, 33, 161.
(8) Mustazza, C.; Borioni, A.; Sestili, I.; Sbraccia, M.;
Rodomonte, A.; Ferretti, R.; Giudice, M. R. D. Chem.
Pharm. Bull. 2006, 54, 611.
(9) Bass, A. D.; Liu, M.; Dai, C.; Gray, K.; Nale, L.; Tevar, S.;
Lee, S.; Liang, L.; Ponery, A.; Yaremko, B.; Smith, E.;
Tang, H.; Sheth, P. R.; Siddiqui, M. A.; Hicklin, D. J.;
Kirschmeier, P. Mol. Cancer Ther. 2010, 9, 2993.
(10) (a) Wood, K. W.; Bergnes, G. Annu. Rep. Med. Chem. 2004,
39, 173. (b) Bergnes, G.; Brejc, K.; Belmont, L. Curr. Top.
Med. Chem. 2005, 5, 127.
(15) (a) Hyodo, S.; Fujita, K.; Kasuyaa, O.; Takahashia, I.;
Uzawab, J.; Koshino, H. Tetrahedron 1995, 24, 6717.
(b) Furumi, K.; Fujioka, T.; Fujii, H.; Okabe, H.; Nakano,
Y.; Matsunaga, H.; Katano, M.; Mori, M.; Mihashi, K.
Bioorg. Med. Chem. Lett. 1998, 8, 93.
(16) Oaksmith, J. M.; Ganem, B. Tetrahedron Lett. 2009, 26,
3497.
(17) Kortylewicz, Z. P.; Nearman, J.; Baranowska-Kortylewicz,
J. J. Med. Chem. 2009, 16, 5124.
(18) Vasilevsky, S. F.; Govdi, A. I.; Sorokina, I. V.; Tolstikova,
T. G.; Baev, D. S.; Tolstikov, G. A.; Mamatuyk, V. I.;
Alabugin, I. V. Bioorg. Med. Chem. Lett. 2011, 21, 62.
(19) (a) Breiner, B.; Schlatterer, J. C.; Kovalenko, S. V.;
Greenbaum, N. L.; Alabugin, I. V. Proc. Natl. Acad. Sci.
U.S.A. 2007, 104, 13016. (b) Breiner, B.; Schlatterer, J. C.;
Kovalenko, S. V.; Greenbaum, N. L.; Alabugin, I. V. Angew.
Chem. Int. Ed. 2006, 45, 3666. (c) Kovalenko, S. V.;
Alabugin, I. V. Chem. Commun. 2005, 1444. (d) Yang, W.-
Y.; Breiner, B.; Kovalenko, S. V.; Ben, C.; Singh, M.; Le
Grand, S. N.; Sang, Q.-X.; Strouse, G. F.; Copland, J. A.;
Alabugin, I. V. J. Am. Chem. Soc. 2009, 131, 11458.
(e) Yang, W.-Y.; Marrone, S. A.; Minors, N.; Zorio, D. A.
R.; Alabugin, I. V. Beilstein J. Org. Chem. 2011, 7, 813.
(20) (a) Foye, W. O. Principidi Chemico Farmaceutica; Piccin:
Padora (Italy), 1991, 416. (b) Andreani, L. L.; Lapi, E. Bull.
Chim. Farm. 1960, 99, 583. (c) Bonsignore, L.; Loy, G.;
Secci, D.; Calignano, A. Eur. J. Med. Chem. 1993, 28, 517.
(21) Ellis, G. P. In The Chemistry of Heterocyclic Compounds:
Chromenes, Chromanes and Chromones; Weissberger, A.;
Taylor, E. C., Eds.; John Wiley: New York (NY), 1977,
Chap. II 11.
(22) Arnesto, D.; Horspool, W. M.; Martin, N.; Ramos, A.;
Seaone, C. J. Org. Chem. 1989, 54, 3069.
(23) (a) Siva Kumar, K.; Mahesh Kumar, P.; Anil Kumar, K.;
Sreenivasulu, M.; Ahamed, A. J.; Rambabu, D.; Rama
Krishna, G.; Malla Reddy, C.; Ravikumar, K.; Shivakumar,
K.; Krishna Priya, K.; Kishore, V. L. P.; Pal, M. Chem.
Commun. 2011, 47, 5010. (b) Bunce, R. A.; Nammalwar, B.
J. Heterocycl. Chem. 2011, 48, 991.
(24) (a) Sashidhara, K. V.; Palnati, G. R.; Avula, S. R.; Kumar,
A. Synlett 2012, 23, 611. (b) Sashidhara, K. V.; Avula, S. R.;
Singh, L. R.; Palnati, G. R. Tetrahedron Lett. 2012, 53,
4880. (c) Sashidhara, K. V.; Kumar, A.; Dodda, R. P.;
Kumar, B. Tetrahedron Lett. 2012, 53, 3281. (d) Sashidhara,
K. V.; Kumar, M.; Kumar, A. Tetrahedron Lett. 2012, 53,
2355. (e) Sashidhara, K. V.; Kumar, A.; Agarwal, S.;
Kumar, M.; Kumar, M.; Sridhar, B. Adv. Synth. Catal. 2012,
354, 1129. (f) Sashidhara, K. V.; Kumar, A.; Rao, K. B.
Tetrahedron Lett. 2011, 52, 5659.
(25) Representative Procedure for the Synthesis of 6-Ethyl-
6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-dione:
Isatoic anhydride (1.0 mmol) was added to a 50-mL round-
bottom flask containing AcOH (10 mL). Ethylamine (1.1
mmol) and 2-formylbenzoic acid (1.0 mmol) were added and
the reaction mixture was heated for 45 min at 110 °C
(initially effervescence was observed due to the generation
of CO2 gas). After completion of the reaction (TLC), the
(11) Audeval, B.; Bouchacourt, P.; Rondier, J. Gaz. Med. Fr.
1988, 95, 70.
(12) Qin, J.; Rao, A.; Chen, X.; Zhu, X.; Liu, Z.; Huang, X.;
Degrado, S.; Huang, Y.; Xiao, D.; Aslanian, R.;
Cheewatrakoolpong, B.; Zhang, H.; Greenfeder, S.; Farley,
C.; Cook, J.; Kurowski, S.; Li, Q.; Heek, M. V.; Chintala,
M.; Wang, G.; Hsieh, Y.; Li, F.; Palani, A. ACS Med. Chem.
Lett. 2011, 2, 171.
(13) Comins, D.; Schilling, S.; Zhang, Y. Org. Lett. 2005, 7, 95.
Synlett 2013, 24, 105–113
© Georg Thieme Verlag Stuttgart · New York

LETTER
reaction mixture was cooled to r.t. and poured into cold H2O
Efficient One-Pot Access to Quinazoline-5,11-diones
113
into cold H2O to precipitate the crude product which was
filtered off. The crude product was purified by column
chromatography (CH2Cl2–hexane, 5:5). The product 6b was
obtained as a pale green solid; yield: 80%; mp 216–218 ºC.
IR (KBr): 2922, 1646, 1218 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 8.07 (d, J = 7.4 Hz, 1 H), 7.80 (d, J = 7.3 Hz, 1
H), 7.69–7.73 (m, 1 H), 7.60–7.65 (m, 1 H), 7.48 (d, J = 8.4
Hz, 1 H), 7.25–7.30 (m, 6 H), 7.05 (d, J = 2.2 Hz, 1 H), 6.27
(s, 1 H). 13C NMR (50 MHz, CDCl3): δ = 166.5, 149.3,
141.7, 138.7, 134.5, 133.3, 133.2, 132.4, 130.4, 129.1,
129.1, 128.5, 128.1, 127.7, 127.4, 123.6, 122.4, 55.7. HRMS
(ESI): m/z [M + H] calcd for C21H13N2ClO: 345.0795; found:
345.0785.
to precipitate the crude product which was filtered off. The
crude product was recrystallized from CHCl3–hexane (2:8)
to give the pure product 4c as a white solid; yield: 91%; mp
156–158 ºC. IR (KBr): 3016, 2854, 1718, 1655, 1487, 1064
cm–1. 1H NMR (300 MHz, CDCl3): δ = 8.09–8.16 (m, 2 H),
8.05 (d, J = 6.9 Hz, 1 H), 7.60–7.80 (m, 4 H), 7.31–7.35 (m,
1 H), 6.25 (s, 1 H), 3.98–4.10 (m, 1 H), 3.69–3.81 (m, 1 H),
1.23 (t, J = 7.0 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ =
164.8, 163.5, 138.1, 136.6, 133.3, 132.8, 132.7, 130.5,
128.9, 125.1, 125.1, 125.0, 120.5, 120.1, 70.2, 37.7, 13.3.
ESI–MS: m/z = 279 [M + H]+.
(26) General Procedure for the Preparation of 3-Chloro-5-
phenylisoindolo[2,1-a]quinazolin-11(6aH)-one (6b): 2-
Amino-5-chlorobenzophenone (1.0 mmol) was added to a
50-mL round-bottom flask containing AcOH (10 mL).
Ammonium acetate (excess) and 2-formylbenzoic acid (1.0
mmol) were then added and the reaction mixture was heated
for 45 min at 110 °C. After completion of the reaction
(TLC), the reaction mixture was cooled to r.t. and poured
(27) (a) Hosseini-Zare, M. S.; Mahdavi, M.; Saeedi, M.; Asadi,
M.; Javanshir, S.; Shafiee, A.; Foroumadi, A. Tetrahedron
Lett. 2012, 53, 3448. (b) Kumar, K. S.; Kumar, P. M.; Rao,
V. S.; Jafar, A. A.; Meda, C. L. T.; Kapavarapu, R.; Parsa, K.
V. L.; Pal, M. Org. Biomol. Chem. 2012, 10, 3098.
(28) Panja, S. K.; Dwivedi, N.; Saha, S. Tetrahedron Lett. 2012,
53, 6176.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 105–113

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