Synthesis of Novel Isoindolo[2,1-a]quinazolinedione Derivatives Containing a 1,2,3-Triazole Ring System

Article abstract of DOI:10.1002/hlca.201500122

A synthesis of isoindolo[2,1-a]quinazolinedione derivatives, coupled with a 1,2,3-triazole ring system, via the reaction of isatoic anhydride, HC=CCH₂NH₂, and 2-formylbenzoic acid is described, which led to the formation of the isoin

Full text of DOI:10.1002/hlca.201500122

Helv. Chim. Acta 2016, 99, 37 – 40
37
FULL PAPER
Synthesis of Novel Isoindolo[2,1-a]quinazolinedione Derivatives Containing a 1,2,3-
Triazole Ring System
by Fatemeh Esmaeili-Marandia), Mina Saeedib)c), Issa Yavaria), Mohammad Mahdavid), and Abbas Shafiee*d)
a) Department of Chemistry, College of Basic Science, Tehran Science and Research Branch, Islamic Azad University, Tehran,
Iran
b) Medicinal Plants Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
c) Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, Tehran, Iran
d) Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of
Medical Sciences, Tehran, Iran (fax: þ 98-21-66461178; e-mail: shafieea@tums.ac.ir)
A synthesis of isoindolo[2,1-a]quinazolinedione derivatives, coupled with a 1,2,3-triazole ring system, via the reaction of
isatoic anhydride, HCꢀCCH2NH2, and 2-formylbenzoic acid is described, which led to the formation of the isoindolo[2,1-a]-
quinazoline-5,11-dione scaffold having a CꢀC bond that participated in a click reaction with various organic azides.
Introduction. – N-Heterocyclic compounds remain an simple three-step reaction starting from isatoic anhydride
attractive topic from both fundamental organic chemistry (Scheme 1).
and medicinal chemistry points of view. They are an
important class of heterocycles with various pharmaceut-
Results and Discussion. – The straightforward ap-
ical applications existing in a wide range of synthetic and proach for the preparation of isoindolo[2,1-a]quinazoline-
natural biologically active molecules. Among various N- coupled 1,2,3-triazoles 9 is shown in Scheme 1. Based on
heterocycles, quinazoline and its derivatives belong to the our experience in the synthesis of a wide range of quinazo-
most important privileged scaffolds due to versatile medic- lines, we chose isatoic anhydride as starting material
inal properties. In this regard, condensed quinazolines have [26 – 30]. Initially, isatoic anhydride (1) reacted with
shown distinguished properties [1][2]. For example, iso- HCꢀCCH2NH2 (2) in H2O at room temperature to give
indoloquinazolines have shown TNF-a inhibitory [3], 2-amino-N-(prop-2-yn-1-yl)benzamide (3). The reaction
sedative, analgesic, and antihypertensive activities [4]. of 3 with 2-formylbenzoic acid (4) was conducted under
Nevertheless, a literature survey indicated that there are various conditions using different solvents and reagents to
only a few reports on the preparation of isoindoloquinazo- obtain 6-(prop-2-yn-1-yl)-6,6a-dihydroisoindolo[2,1-a]qui-
lines [5 – 7]. Some derivatives were synthesized via the nazoline-5,11-dione (5). Some results are shown in Table 1.
reaction of oxo acids with anthranilic acid, anthranilamides, The tests revealed that using TsOH (20 mol-%) in EtOH
orthanilamides, or salicylamide [8]. Recently, isoindolo- under reflux afforded 5 in high yield (85%).
quinazolinediones have been synthesized via the reaction Next, compound 5, possessing a potent CꢀC bond, was
of isatoic anhydride, amines, and 2-formylbenzoic acid readily converted to the desired product 9 via click reaction
under different conditions [3][9][10]. [17]. For this purpose, various organic azides, 8, were
1,2,3-Triazoles are known as a promising class of N- prepared by the reaction of different benzyl chlorides/
heterocycles. They have exhibited cytotoxic [11], anti-HIV- bromides, 6, and NaN3 (7) in the presence of Et3N in a
1 [12], anti-influenza [13], antiplatelet [14], acetylcholi-
nesterase inhibitory [15], and antituberculosis [16] activ-
ities. The main method for the synthesis of the 1,2,3-triazole
ring follows the click reaction described by Sharpless et al.
[17] and modified procedures [18 – 20].
Table 1. Investigation of Various Conditions for the Formation of 5
Entry
Solvent
Reagent
Yield [%]a)
1
2
3
4
5
6
7
EtOH
EtOH
EtOH
MeCN
MeCN
CH2Cl2
Toluene
TsOH
85
70
75
65
65
30
35
Considering the fact that combination of two or
more pharmacophores has been a versatile tool for drug
discovery developments, we focused on an isoindolo-
quinazoline-1,2,3-triazole hybrid which has not been re-
ported in the literature. Herein, in continuation of our work
on the synthesis of novel N-heterocycles [21 – 25], we
report the design and synthesis of novel isoindolo[2,1-a]-
quinazolines containing a 1,2,3-triazole ring system via a
DABCOb)
K2CO3
TsOH
K2CO3
TsOH
K2CO3
a) Yield of isolated product. b) DABCO, 1,4-diazabicyclo[2.2.2]octane.
DOI: 10.1002/hlca.201500122
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Helv. Chim. Acta 2016, 99, 37 – 40
Scheme 1. Synthesis of Isoindolo[2,1-a]quinazoline-Coupled 1,2,3-Triazoles 9
mixture of H2O/tBuOH at room temperature. Then, 5, anhydride (1) and HCꢀCCH2NH2 (2) gives 2-amino-N-
sodium ascorbate, and a catalytic amount of CuSO4 (7 mol- (prop-2-yn-1-yl)benzamide (3) by elimination of CO2.
%) were added to the freshly prepared azides 8 leading to Then, reaction of 3 and 2-formylbenzoic acid (4) in the
the formation of different isoindolo[2,1-a]quinazoline- presence of TsOH leads to the formation of imine
dione-coupled 1,2,3-triazoles 9.
intermediate 10 which undergoes nucleophilic addition of
The scope of the reaction was studied by varying azide the NH N-atom to afford 11. Next, nucleophilic attack of
derivatives 8 (Table 2). It was clear that all azide deriva- the ring N-atom on the activated C¼O group of the
tives 8 possessing electron-donating and electron-with- carboxylic acid and loss of H2O leads to the formation of
drawing groups as well as halogens underwent a click five-membered intermediates 12 and 13, respectively.
reaction to afford products 9. Also, the structures of Then, proton transfer gives 6-(prop-2-yn-1-yl)-6,6a-dihy-
products 9 were confirmed using IR and 1H- and 13C-NMR droisoindolo[2,1-a]quinazoline-5,11-dione (5). Finally,
spectroscopy, as well as chemical analysis.
CuII-catalyzed reaction of 5 and freshly prepared azide
A plausible mechanism for the formation of product 9 is derivatives 8 affords products 9 via click reaction [17].
shown in Scheme 2 [3][10]. Initially, reaction of isatoic
Conclusions. – In summary, we described an operation-
ally simple three-step procedure for the synthesis of novel
isoindolo[2,1-a]quinazolinedione-coupled 1,2,3-triazoles
Table 2. Synthesis of Isoindolo[2,1-a]quinazoline-Coupled 1,2,3-Tri-
azoles 9
starting from isatoic anhydride. Good yields (65 – 90%)
and user-friendly procedures encourage organic and me-
dicinal chemists to profit from both synthetic and biological
aspects.
We gratefully acknowledge financial support from the Research
Council of Tehran University of Medical Sciences and the Iran National
Science Foundation (INSF).
Entry
Ar
Product 9
Yield [%]a)
Experimental Part
1
2
3
4
5
6
7
8
Ph
9a
9b
9c
9d
9e
9f
9g
9h
80
85
80
90
85
70
70
65
2-MeÀC6H4
4-FÀC6H4
2-ClÀC6H4
2,3-Cl2ÀC6H3
3,4-Cl2ÀC6H3
2-BrÀC6H4
2-NO2ÀC6H4
General. M.p.: Kofler hot stage apparatus; uncorrected. Thin layer
chromatography (TLC): petroleum ether/AcOEt. IR Spectra: Nicolet
.
Magna FTIR 550 spectrophotometer; KBr; n˜ in cmÀ1 1H- and
13C-NMR spectra: Bruker FT-500 (500 and 125 MHz, resp.); in
(D6)DMSO; d in ppm rel. to Me4Si as internal standard, J in Hz.
Elemental analysis: VarioEL (Elementar Analysensysteme GmbH);
CHNS mode; in %.
Synthesis of 2-Amino-N-(prop-2-yn-1-yl)benzamide (3). A mix-
ture of isatoic anhydride (1; 10 mmol) and HCꢀCCH2NH2 (2;
a) Yield of isolated product.
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Helv. Chim. Acta 2016, 99, 37 – 40
39
Scheme 2. A Plausible Mechanism for the Formation of Products 9
10 mmol) in H2O (20 ml) was stirred at r.t. for 4 h. After completion of
the reaction (checked by TLC), the resulting off-colorless precipitate
was filtered off and used for the next reaction steps without further
purification.
Synthesis of 6-(Prop-2-yn-1-yl)-6,6a-dihydroisoindolo[2,1-a]qui-
nazoline-5,11-dione (5). A mixture of 2-amino-N-(prop-2-yn-1-yl)-
benzamide (3; 1 mmol), 2-formylbenzoic acid (4; 1 mmol), and TsOH
(20 mol-%) in EtOH (10 ml) was heated under reflux for 12 h. After
completion of the reaction (checked by TLC), the mixture was cooled
to r.t. and poured into cold H2O. The precipitated product was filtered
off, washed with H2O, and used for the next reaction steps without
further purification.
6,6a-Dihydro-6-{[1-(2-methylbenzyl)-1H-1,2,3-triazol-4-yl]meth-
yl}isoindolo[2,1-a]quinazoline-5,11-dione (9b). Yield: 0.37 g (85%).
Colorless crystals. M.p. 198 – 2018. IR: 3126, 3072, 2959, 1724, 1647,
1603. 1H-NMR: 2.24 (s, Me); 4.78 (d, J ¼ 16.0, 1 H of CH2); 5.18 (d, J ¼
16.0, 1 H of CH2); 5.53 (s, 2 H of CH2); 6.62 (s, CH); 6.90 (d, J ¼ 6.0,
HÀC(3’)); 7.16 – 7.21 (m, HÀC(4’ – 6’)); 7.38 (t, J ¼ 6.0, HÀC(3)); 7.69 –
7.73 (m, HÀC(7 – 9)); 7.86 (s, H of triazole); 7.91 (d, J ¼ 6.0, HÀC(1));
7.99 – 8.04 (m, HÀC(2,10)); 8.14 (d, J ¼ 6.0, HÀC(4)). 13C-NMR: 18.6;
38.0; 50.9; 70.3; 119.8; 119.9; 123.5; 124.2; 125.0; 126.2; 126.4; 128.2;
128.4; 128.5; 130.3; 130.6; 131.8; 133.0; 133.6; 134.1; 136.2; 136.7; 138.1;
143.5; 163.1; 164.4. Anal. calc. for C26H21N5O2 (435.49): C 71.71, H 4.86,
N 16.08; found: C 71.90, H 4.71, N 16.23.
Synthesis of 1,2,3,4-Tetrahydroquinazolinone Derivatives (9). Typ-
ical Procedure. A soln. of benzyl chloride/bromide derivative 6
(1.1 mmol), NaN3 (7; 0.9 mmol), and Et3N (1.3 mmol) in H2O (4 ml)/
tBuOH (4 ml) was stirred at r.t. for 1 h. Subsequently, a mixture of 6-
(prop-2-yn-1-yl)-6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-dione
(5; 1 mmol), sodium ascorbate (0.1 mmol), and CuSO4 (7 mol-%) was
added to the freshly prepared azide derivative 8 and the mixture was
stirred at r.t. for 24 h. Upon completion of the reaction (monitored by
TLC), the mixture was diluted with H2O and poured into crushed ice.
The precipitated product was filtered off and washed with cold H2O. All
products were recrystallized from petroleum ether/AcOEt 1:1 to give
pure samples.
6-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]-6,6a-dihydroisoindo-
lo[2,1-a]quinazoline-5,11-dione (9a). Yield: 0.33 g (80%). Colorless
crystals. M.p. 232 – 2348. IR: 3125, 3071, 2959, 1723, 1645, 1603.
1H-NMR: 4.76 (d, J ¼ 16.0, 1 H of CH2); 5.19 (d, J ¼ 16.0, 1 H of
CH2); 5.53 (s, 2 H of CH2); 6.62 (s, CH); 7.19 – 7.20 (m, 1 H of Ph,
HÀC(3)); 7.35 – 7.36 (m, 4 H of Ph); 7.69 – 7.75 (m, HÀC(7 – 9)); 7.91 (d,
J ¼ 6.5, HÀC(1)); 8.00 – 8.04 (m, HÀC(2,10), H of triazole); 8.14 (d, J ¼
6.5, HÀC(4)). 13C-NMR: 38.0; 52.7; 70.3; 119.8; 119.9; 123.6; 124.2;
125.0; 126.4; 127.7; 128.0; 128.5; 128.7; 130.6; 131.8; 133.0; 133.6; 136.0;
136.7; 138.1; 143.6; 163.2; 164.4. Anal. calc. for C25H19N5O2 (421.46): C
71.25, H 4.54, N 16.62; found: C 71.36, H 4.71, N 16.48.
6-{[1-(4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl]methyl}-6,6a-dihy-
droisoindolo[2,1-a]quinazoline-5,11-dione (9c). Yield: 0.35 g (80%).
Colorless crystals. M.p. 220 – 2218. IR: 3125, 3055, 2959, 1726, 1642,
1603. 1H-NMR: 4.76 (d, J ¼ 16.0, 1 H of CH2); 5.18 (d, J ¼ 16.0,
1 H of CH2); 5.52 (s, 2 H of CH2); 6.62 (s, CH); 7.19 (d, J ¼ 8.5,
HÀC(3’,5’)); 7.26 – 7.29 (m, HÀC(2’,6’)); 7.38 (t, J ¼ 7.5, HÀC(3)); 7.68 –
7.76 (m, HÀC(7 – 9)); 7.91 (d, J ¼ 7.5, HÀC(1)); 7.99 (s, H of triazole);
7.99 – 8.04 (m, HÀC(2,10)); 8.13 (d, J ¼ 7.5, HÀC(4)). 13C-NMR:
38.0; 51.9; 70.3; 115.5 (d, J ¼ 21.2); 119.8; 120.0; 123.5; 124.2; 125.0;
126.4; 128.5; 130.1 (d, J ¼ 8.7); 130.6; 131.8; 132.2; 133.0; 133.6; 136.7;
138.2; 143.7; 161.8 (d, J ¼ 242.5); 163.2; 164.4. Anal. calc. for
C25H18FN5O2 (439.45): C 68.33, H 4.13, N 15.94; found: C 68.50, H
4.22, N 16.18.
6-{[1-(2-Chlorobenzyl)-1H-1,2,3-triazol-4-yl]methyl}-6,6a-dihy-
droisoindolo[2,1-a]quinazoline-5,11-dione (9d). Yield: 0.41 g (90%).
Colorless crystals. M.p. 173 – 1758. IR: 3114, 3064, 2958, 1719, 1653,
1601. 1H-NMR: 4.81 (d, J ¼ 16.5, 1 H of CH2); 5.20 (d, J ¼ 16.5, 1 H of
CH2); 5.60 (s, 2 H of CH2); 6.63 (s, CH); 7.30 (t, J ¼ 7.5, HÀC(3)); 7.36 –
7.40 (m, HÀC(4’ – 6’)); 7.66 – 7.77 (m, HÀC(7 – 9,3’)); 7.90 (d, J ¼ 7.5,
HÀC(1)); 7.92 (s, H of triazole); 8.00 – 8.04 (m, HÀC(2,10)); 8.13 (d, J ¼
7.5, HÀC(4)). 13C-NMR: 38.0; 52.8; 70.3; 119.9; 120.0; 122.8; 123.9;
124.2; 125.0; 126.4; 128.2; 128.5; 130.0; 130.3; 130.6; 131.9; 132.8; 133.0;
133.6; 134.9; 136.7; 138.2; 143.6; 163.2; 164.4. Anal. calc. for
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Helv. Chim. Acta 2016, 99, 37 – 40
C25H18ClN5O2 (455.90): C 65.86, H 3.98, N 15.36; found: C 65.70, H
4.18, N 15.41.
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6-{[1-(2,3-Dichlorobenzyl)-1H-1,2,3-triazol-4-yl]methyl}-6,6a-di-
hydroisoindolo[2,1-a]quinazoline-5,11-dione (9e). Yield: 0.41 g
(85%). Colorless crystals. M.p. 248 – 2508. IR: 3128, 3055, 2923, 2853,
1
1727, 1643, 1601. H-NMR: 4.83 (d, J ¼ 16.0, 1 H of CH2); 5.19 (d, J ¼
16.0, 1 H of CH2); 5.67 (s, 2 H of CH2); 6.63 (s, CH); 6.91 (d, J ¼ 7.5,
HÀC(6’)); 7.35 – 7.40 (m, HÀC(3,5’)); 7.65 – 7.76 (m, HÀC(7 – 9,4’)); 7.90
(d, J ¼ 7.5, HÀC(1)); 7.95 (s, H of triazole); 8.00 – 8.04 (m, HÀC(2,10));
8.13 (d, J ¼ 7.5, HÀC(4)). 13C-NMR: 38.0; 51.0; 70.3; 119.8; 120.0;
124.0; 124.2; 125.0; 126.4; 128.5; 130.4; 130.5; 130.6; 131.8; 132.1; 133.0;
133.6; 135.9; 136.0; 136.7; 137.2; 138.2; 143.7; 163.2; 164.4. Anal. calc.
for C25H17Cl2N5O2 (490.34): C 61.24, H 3.49, N 14.28; found: C 61.42, H
3.28, N 14.18.
6-{[1-(3,4-Dichlorobenzyl)-1H-1,2,3-triazol-4-yl]methyl}-6,6a-di-
hydroisoindolo[2,1-a]quinazoline-5,11-dione (9f). Yield: 0.34 g (70%).
Colorless crystals. M.p. 220 – 2228. IR: 3126, 3056, 2959, 1726, 1642,
1603. 1H-NMR: 4.79 (d, J ¼ 16.5, 1 H of CH2); 5.18 (d, J ¼ 16.5, 1 H of
CH2); 5.54 (s, 2 H of CH2); 6.62 (s, CH); 7.17 (d, J ¼ 8.0, HÀC(6’)); 7.39
(t, J ¼ 7.5, HÀC(3)); 7.56 (s, HÀC(2’)); 7.67 (d, J ¼ 8.0, HÀC(5’)); 7.71 –
7.75 (m, HÀC(7 – 9)); 7.89 (d, J ¼ 7.5, HÀC(1)); 7.96 – 8.04 (m,
HÀC(2,10), H of triazole); 8.12 (d, J ¼ 7.5, HÀC(4)). 13C-NMR: 38.3;
51.3; 70.3; 119.9; 120.0; 123.7; 124.2; 125.0; 126.3; 128.3; 128.5; 130.1;
130.6; 131.0; 131.3; 131.8; 133.0; 133.6; 135.2; 137.0; 137.2; 138.2; 143.8;
163.1; 164.3. Anal. calc. for C25H17Cl2N5O2 (490.34): C 61.24, H 3.49, N
14.28; found: C 61.11, H 3.60, N 14.33.
6-{[1-(2-Bromobenzyl)-1H-1,2,3-triazol-4-yl]methyl}-6,6a-dihy-
droisoindolo[2,1-a]quinazoline-5,11-dione (9g). Yield: 0.35 g (70%).
Colorless crystals. M.p. 170 – 1718. IR: 3115, 3062, 2959, 1721, 1656,
1602. 1H-NMR: 4.81 (d, J ¼ 16.0, 1 H of CH2); 5.19 (d, J ¼ 16.0, 1 H of
CH2); 5.60 (s, 2 H of CH2); 6.63 (s, CH); 6.91 (d, J ¼ 7.5, HÀC(6’));
7.29 – 7.38 (m, HÀC(3,4’,5’)); 7.66 – 7.77 (m, HÀC(7 – 9,3’)); 7.90 – 7.92
(m, HÀC(1), H of triazole); 8.00 – 8.04 (m, HÀC(2,10)); 8.13 (d, J ¼ 7.5,
HÀC(4)). 13C-NMR: 38.1; 52.8; 70.3; 119.8; 120.0; 122.7; 123.9; 124.2;
125.0; 126.4; 128.2; 128.5; 130.0; 130.3; 130.6; 131.9; 132.8; 133.0; 133.6;
134.9; 136.7; 138.2; 143.6; 163.2; 164.4. Anal. calc. for C25H18BrN5O2
(500.36): C 60.01, H 3.63, N 14.00; found: C 59.88, H 3.50, N 14.21.
6,6a-Dihydro-6-{[1-(2-nitrobenzyl)-1H-1,2,3-triazol-4-yl]methyl}-
isoindolo[2,1-a]quinazoline-5,11-dione (9h). Yield: 0.30 g (65%). Col-
orless crystals. M.p. 160 – 1618. IR: 3155, 3060, 2959, 1726, 1655, 1604.
1H-NMR: 4.82 (d, J ¼ 16.0, 1 H of CH2); 5.21 (d, J ¼ 16.0, 1 H of CH2);
5.89 (s, 2 H of CH2); 6.65 (s, CH); 6.91 (d, J ¼ 7.5, HÀC(6’)); 7.39 (t, J ¼
7.5, HÀC(3)); 7.62 – 7.77 (m, HÀC(7 – 9,4’,5’)); 7.91 (d, J ¼ 7.5, HÀC(1));
7.97 (s, H of triazole); 7.99 – 8.05 (m, HÀC(2,10)); 8.13 – 8.16 (m,
HÀC(2,3’)). 13C-NMR: 38.0; 50.0; 70.1; 119.8; 120.0; 123.2; 124.6;
125.0; 126.5; 128.2; 128.5; 129.5; 130.0; 130.3; 130.6; 131.9; 132.7; 133.0;
133.5; 134.3; 138.2; 143.1; 150.0; 163.1; 164.1. Anal. calc. for C25H18N6O4
(466.46): C 64.37, H 3.89, N 18.02; found: C 64.25, H 3.71, N 18.18.
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Received May 18, 2015
Accepted September 30, 2015
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