Synthesis of isoindolo[2,1-a]quinazoline-5,11-dione derivatives via the reductive one-pot reaction of N-substituted 2-nitrobenzamides and 2-formylbenzoic acids

Article abstract of DOI:10.1002/hlca.201200199

Various isoindolo[2,1-a]quinazoline-5,11-dione derivatives 3 were synthesized in good yields by means of the reductive reaction of N-substituted 2-nitrobenzamides 1 and 2-formylbenzoic acids 2 in the presence of SnCl ₂·2 H₂O under reflux in EtOH (Scheme, Table). The procedure needed two steps, the reduction of the nitro group of the 2-nitrobenzamide and ring closure by nucleophilic addition of the NH₂ group to both the formyl and carboxylic acid C=O groups. Copyright

Full text of DOI:10.1002/hlca.201200199

Helvetica Chimica Acta – Vol. 96 (2013)
419
Synthesis of Isoindolo[2,1-a]quinazoline-5,11-dione Derivatives via the
Reductive One-Pot Reaction of N-Substituted 2-Nitrobenzamides and
2-Formylbenzoic Acids
by Mohammad Mahdavia), Ramin Najafib), Mina Saeedia), Eskandar Alipourb), Abbas Shafieea), and
Alireza Foroumadi*a)
a) Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research
Center, Tehran University of Medicinal Sciences, Tehran 14176, Iran
(phone: þ 98-21-66406757; fax: þ 98-21-66954708; e-mail: aforoumadi@yahoo.com)
b) Department of Chemistry, Islamic Azad University, Tehran-North Branch, Zafar St., Tehran, Iran
Various isoindolo[2,1-a]quinazoline-5,11-dione derivatives 3 were synthesized in good yields by
means of the reductive reaction of N-substituted 2-nitrobenzamides 1 and 2-formylbenzoic acids 2 in the
presence of SnCl2 · 2 H2O under reflux in EtOH (Scheme, Table). The procedure needed two steps, the
reduction of the nitro group of the 2-nitrobenzamide and ring closure by nucleophilic addition of the NH2
group to both the formyl and carboxylic acid C¼O groups.
Introduction. – Isoindolin-1-ones (¼2,3-dihydro-1H-isoindol-1-ones) and their
derivatives exhibit important physiological and chemotherapeutic activities [1]. Also
they have shown a wide range of activities including antioxidant [2], antimicrobial [3],
and anticancer activity [4]. Some 2-[3-(cyclopentyloxy)-4-methoxyphenyl]isoindolin-
1-one derivatives were synthesized and screened for a developed allosteric mGluR1
antagonist by Park and co-workers [5]. They are potent inhibitors of TNF-a production
in LPS-stimulated RAW264.7 cells.
The 2,3-dihydroquinazolin-4(1H)-one-centered compounds play also an important
role in organic chemistry, as key structural units in many natural products and
important pharmaceuticals [6][7]. A considerable number of 2,3-dihydroquinazolin-
4(1H)-ones are well-known as antibacterial [8], vasodilatory [9], antispermatogenic
[10], antifibrillatory [11], and analgesic [12] agents.
Although isoindolin-1-ones and 2,3-dihydroquinazolin-4(1H)-ones individually
possess important biological properties, to the best of our knowledge, only a few
studies have been published on the synthesis and biological activities of fused isoindolo-
quinazolinone derivatives [13 – 19]. Thus, herein, in continuation of our work on the
synthesis new heterocycles [20], particularly bioactive compounds [21], we wish to
report an efficient route for the synthesis of isoindolo[2,1-a]quinazoline-5,11-dione
derivatives 3 via reaction of 2-nitrobenzamides 1 and 2-formylbenzoic acids 2 in the
presence of SnCl2 · 2 H2O under reflux conditions in EtOH (Scheme). The reductive
reaction of 2-nitrobenzamides in the presence of SnCl2 with diverse substrates has been
investigated, and proficient routes for the synthesis of heterocyclic scaffolds have been
provided [22 – 24].
ꢀ 2013 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Helvetica Chimica Acta – Vol. 96 (2013)
Scheme. Synthesis of Isoindolo[2,1-a]quinazoline-5,11-dione-Derivatives 3. For R1 and R2, see Table.
Results and Discussion. – We began our study with the reaction of N-(furan-2-
ylmethyl)-2-nitrobenzamide (1a) and 2-formylbenzoic acid (2a), investigating the
influence of different amounts of SnCl2 · 2 H2O and solvents under various conditions
with the aim of improving the yield of the product 3a. It was found that the use of
1 mmol of each starting material 1a and 2a and 4 mmol of SnCl2 · 2 H2O in refluxing
EtOH gave the optimized conditions, and 3a was obtained in 85% yield (Table).
With these results in hand, reactions were performed with various 2-nitrobenz-
amides 1 to explore the substrate scope with regard to two 2-formylbenzoic acid
derivatives 2a (R2 ¼ H) and 2b (R2 ¼ MeO; Table). It should be noted that all the
reactions reached completion within 8 h, furnishing the products 3a – 3h in very good
yields.
The structures of compounds 3a – 3h were elucidated from their elemental analysis,
mass, IR, and 1H-, and 13C-NMR spectra.
The reaction proceded in two steps, first the reduction of the NO2 group of 1 and
then ring closure by nucleophilic addition of the NH2 group to both the CHO and
COOH groups of 2.
In conclusion, we developed the direct preparation of isoindolo[2,1-a]quinazoline-
5,11-dione derivatives 3 in a one-pot reductive reaction of N-substituted 2-nitro-
benzamides 1 and 2-formylbenzoic acids 2. Availability of the starting materials, one-
pot procedure, and high yield provide a very useful route to construct differently
substituted isoindolo[2,1-a]quinazoline-5,11-diones.
We gratefully acknowledge the partial financial support from the Medicinal Sciences Research
Council of the Tehran University and the Iran National Science Foundation (INSF).
Experimental Part
General. M.p.: Kofler hot-stage apparatus; uncorrected. IR Spectra: Shimadzu-470 spectropho-
1
tometer; in KBr; ˜n in cmꢀ1. H- and 13C-NMR Spectra: Bruker FT-500; CDCl3 solns.; d in ppm rel. to
Me4Si as internal standard, J in Hz. MS: Agilent-Technology (HP) mass spectrometer, ionization
potential 70 eV; in m/z. Elemental analysis: VarioEL CHNS mode (Elementar Analysensystem GmbH).
Isoindolo[2,1-a]quinazoline-5,11-dione Derivatives 3: Typical Procedure. A soln. of 2-nitrobenz-
amide 1 (1 mmol), 2-formylbenzoic acid 2 (1 mmol), and SnCl2 · H2O (4 mmol) in EtOH (8 ml) was
stirred under reflux for 8 h. The reaction was quenched with 3% HCl soln. (15 ml) and the resulting
mixture filtered. The crude product was purified by recrystallization from EtOH/H2O 4 :1: pure 3.
6-(Furan-2-ylmethyl)-6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-dione (3a) [18]. White crystals.
M.p. 166 – 1688. IR: 1721, 1668, 1602, 1488. 1H-NMR: 8.04 – 7.38 (m, 8 arom. H); 7.53 (d, J ¼ 3.0, 1 H, fur);

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Table. Synthesis of Isoindolo[2,1-a]quinazoline-5,11-dione Derivatives 3
R1 in 2-Nitrobenzamide 1
R2
H
Product
Yield [%]a)
85
3a [18]
H
3b
90
80
MeO
3c [25]
MeO
MeO
3d
3e
80
80
H
3f [14]
85
80
MeO
3g
H
3h
85

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Helvetica Chimica Acta – Vol. 96 (2013)
6.63 (s, CH); 6.32 (t, J ¼ 3.0, 1 H, fur); 6.14 (d, J ¼ 3.0, 1 H, fur); 5.11 (d, J ¼ 16.8, 1 H, CH2); 4.76 (d, J ¼
16.8, 1 H, CH2). 13C-NMR: 164.3; 163.0; 150.4; 142.3; 138.1; 136.6; 133.6; 130.6; 128.6; 133.1; 126.1; 125.1;
124.2; 121.4; 119.9; 119.8; 110.5; 107.4; 70.2; 45.0. MS: 330 (Mþ), 249, 235, 207, 179. Anal. calc. for
C20H14N2O3 (330.34): C 72.72, H 4.27, N 8.48; found: C 72.52, H 4.39, N 8.37.
6,6a-Dihydro-6-(pyridin-2-ylmethyl)isoindolo[2,1-a]quinazoline-5,11-dione (3b): White crystals.
1
M.p. 212 – 2148. IR: 1721, 1660, 1597. H-NMR: 8.49 – 7.23 (m, 12 arom. H); 6.81 (s, CH); 5.26 (d, J ¼
17.2, 1 H, CH2); 4.90 (d, J ¼ 17.2, 1 H, CH2). 13C-NMR: 164.3; 163.3; 156.7; 149.0; 138.1; 136.9; 136.8;
133.5; 132.8; 131.9; 130.5; 128.6; 125.9; 125.0; 124.1; 122.2; 121.2; 119.9; 119.8; 70.6; 47.5. MS: 341 (Mþ),
249, 207, 93. Anal. calc. for C21H15N3O2 (341.36): C 73.89, H 4.43, N 12.31; found: C 73.67, H 4.61, N 12.50.
6-(Furan-2-ylmethyl)-6,6a-dihydro-9,10-dimethoxyisoindolo[2,1-a]quinazoline-5,11-dione (3c) [25]:
White crystals. M.p. 181 – 1838. IR: 1731, 1660, 1601. 1H-NMR: 8.01 – 7.36 (m, 6 arom. H); 7.56 (d, J ¼ 2.0,
1 H, fur); 6.46 (s, CH); 6.36 (dd, J ¼ 3.0, 2.0, 1 H, fur); 6.17 (d, J ¼ 3.0, 1 H, fur); 5.06 (d, J ¼ 16.7, 1 H,
CH2); 4.64 (d, J ¼ 16.7, 1 H, CH2); 3.91 (s, MeO); 3.88 (s, MeO). 13C-NMR: 162.9; 162.5; 153.8; 150.5;
147.1; 142.3; 136.7; 133.4; 130.3; 128.5; 124.9; 123.8; 121.6; 120.2; 120.0; 117.4; 110.6; 107.3; 69.0; 61.7;
56.4; 47.2. MS: 390 (Mþ), 295, 280, 252, 224. Anal. calc. for C22H18N2O5 (390.39): C 67.69, H 4.65, N 7.18;
found: C 67.50, H 4.75, N 7.35.
6-Benzyl-6,6a-dihydro-9,10-dimethoxyisoindolo[2,1-a]quinazoline-5,11-dione (3d): White crystals.
M.p. 197 – 2008. IR: 1709, 1655, 1601, 1491. 1H-NMR: 8.05 – 7.07 (m, 11 arom. H); 6.54 (s, CH); 5.06 (d,
J ¼ 16.9, 1 H, CH2); 4.90 (d, J ¼ 16.9, 1 H, CH2); 3.86 (s, MeO); 3.81 (s, MeO). 13C-NMR: 163.2; 162.4;
153.6; 146.9; 137.3; 136.8; 133.3; 130.2; 128.6; 128.4; 126.6; 126.0; 125.0; 123.8; 121.5; 120.2; 120.1; 117.3;
69.1; 61.7; 56.3; 45.5. MS: 400 (Mþ), 296, 252, 224, 179, 152. Anal. calc. for C24H20N2O4 (400.43): C 71.99,
H 5.03, N 7.00; found: C 72.15, H 5.22, N 7.10.
6-(4-Chlorobenzyl)-6,6a-dihydro-9,10-dimethoxyisoindolo[2,1-a]quinazoline-5,11-dione (3e): White
crystals. M.p. 180 – 1828. IR: 1725, 1658, 1605, 1490. 1H-NMR: 8.04 – 7.07 (m, 10 arom. H); 6.53 (s, CH);
4.97 (s, CH2); 3.86 (s, MeO); 3.82 (s, MeO). 13C-NMR: 163.2; 162.4; 153.7; 147.0; 136.7; 136.5; 133.3;
131.1; 130.2; 128.6; 128.3; 127.9; 125.0; 123.7; 121.6; 120.2; 120.1; 117.3; 69.1; 61.7; 56.3; 45.0. MS: 434
(Mþ), 436 ([M þ 2]þ), 295, 280, 252, 125. Anal. calc. for C24H19ClN2O4 (434.87): C 66.29, H 4.40, N 6.44;
found: C 66.44, H 4.55, N 6.65.
6-(4-Chlorobenzyl)-6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-dione (3f) [14]: White crystals.
M.p. 180 – 1828. IR: 1718, 1661, 1605, 1491. 1H-NMR: 8.05 – 7.07 (m, 12 arom. H); 6.71 (s, CH); 5.08 (d,
J ¼ 17.2, 1 H, CH2); 5.01 (d, J ¼ 17.2, 1 H, CH2). 13C-NMR: 164.3; 163.3; 137.9; 136.6; 136.5; 133.5; 132.9;
131.7; 131.1; 130.5; 128.6; 128.2; 127.8; 126.1; 125.1; 124.1; 119.9; 70.2; 45.1. MS: 374 (Mþ), 376 ([M þ
2]þ), 280, 235, 167, 149. Anal. calc. for C22H15ClN2O2 (374.82): C 70.50, H 4.03, N 7.47; found: C 69.95,
H 4.20, N 7.50.
6,6a-Dihydro-9,10-dimethoxy-6-(pyridin-2-ylmethyl)isoindolo[2,1-a]quinazoline-5,11-dione (3g):
1
White crystals. M.p. 210 – 2128. IR: 1725, 1658, 1602, 1590. H-NMR: 8.50 – 7.12 (m, 10 arom. H); 6.64
(s, CH); 5.22 (d, J ¼ 17.2, 1 H, CH2); 4.82 (d, J ¼ 17.2, 1 H, CH2); 3.82 (s, MeO); 3.89 (s, MeO). 13C-NMR:
163.2; 162.5; 156.7; 153.7; 149.0; 147.0; 137.0; 136.9; 133.3; 130.3; 128.5; 124.9; 123.9; 122.2; 121.4; 121.3;
120.1; 117.2; 69.5; 61.7; 56.3; 47.2. MS: 401 (Mþ), 309, 225, 190, 69. Anal. calc. for C23H19N3O4 (401.41): C
68.82, H 4.77, N 10.47; found: C 69.05, H 4.85, N 10.55.
6-(2-Chlorobenzyl)-6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-dione (3h): White crystals. M.p.
185 – 1888. IR: 1709, 1686, 1602, 1490. 1H-NMR: 8.23 – 7.05 (m, 12 arom. H); 6.37 (s, CH); 5.27 (d, J ¼
17.5, 1 H, CH2); 5.04 (d, J ¼ 17.5, 1 H, CH2). 13C-NMR: 164.9; 164.2; 137.4; 137.0; 133.9; 133.6; 132.7;
132.4; 132.1; 130.6; 129.8; 129.5; 128.4; 127.2; 126.8; 125.4; 124.9; 124.8; 120.3; 120.0; 70.7; 44.7. MS: 374
(Mþ), 376 ([M þ 2]þ), 280, 235, 149. Anal. calc. for C24H19ClN2O4 (374.82): C 70.50, H 4.03, N 7.47;
found: C 70.77, H 4.32, N 6.60.
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