Synthesis of Isoindolo[2,1-a]quinazoline, Isoindolo[2,1-a]pyrrolo [2,1-c]quinoxalinone, and Indolo[1,2-a]isoindolo[1,2-c]quinoxalinone Derivatives in a Deep Eutectic Solvent

Article abstract of DOI:10.1055/s-0036-1588074

2-Formylbenzoic acid reacts with various derivatives of 2-aminobenzamide, 2-(1H-pyrrol-1-yl)aniline or 2-(1H-indol-1-yl)aniline in a deep eutectic solvent to give the corresponding derivatives of 6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-dione, isoindolo[2,1-a]pyrrolo[2,1-c]quinoxalin-10(14bH)-one, and indolo[1,2-a]isoindolo[1,2-c]quinoxalin-11(15bH)-one, respectively . This protocol is operationally simple, mild, and efficient.

Full text of DOI:10.1055/s-0036-1588074

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
letter
A
R. V. Devi et al.
Letter
Synlett
Synthesis of Isoindolo[2,1-a]quinazoline, Isoindolo[2,1-a]pyrrolo
[2,1-c]quinoxalinone, and Indolo[1,2-a]isoindolo[1,2-c]quinoxali-
none Derivatives in a Deep Eutectic Solvent
Rajkumari Vijilata Devi◊
Ashok M. Garande◊
Prakash M. Bhate*
Department of Dyestuff Technology, Institute of Chemical Technology,
N. P. Marg, Matunga, Mumbai 400 019, Maharashtra, India
pm.bhate@ictmumbai.edu.in
◊These authors contributed equally.
Received: 14.07.2016
Accepted after revision: 31.08.2016
Published online: 19.09.2016
ods for preparing indoloquinoxalines include a photocy-
clization strategy,27 ruthenium-catalyzed C–H bond activa-
tion and cyclization,28 and a modified Pictet–Spengler reac-
tion catalyzed by TsOH with benzotriazole as an additive.24
The synthesis of imidazoquinoxalines through a Pictet–
Spengler reaction on a solid phase has been reported.29
However, these protocols suffer from various drawbacks,
such as extended reaction times in the range of 7–15
hours,9,14,16,17 low to moderate yields,11 or the use of organic
solvents such as EtOH,9,17 acetic acid,10,11,18 THF,13,24 or tolu-
ene.24
DOI: 10.1055/s-0036-1588074; Art ID: st-2016-d0457-l
Abstract 2-Formylbenzoic acid reacts with various derivatives of
2-aminobenzamide, 2-(1H-pyrrol-1-yl)aniline or 2-(1H-indol-1-yl)ani-
line in a deep eutectic solvent to give the corresponding derivatives of
6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-dione,
isoindolo[2,1-
a]pyrrolo[2,1-c]quinoxalin-10(14bH)-one, and indolo[1,2-a]isoindo-
lo[1,2-c]quinoxalin-11(15bH)-one, respectively . This protocol is opera-
tionally simple, mild, and efficient.
Key words eutectics, formylbenzoic acid, isoindoloquinazolinediones,
isoindolopyrroloquinoxalinones, indoloisoindoloquinoxalinones deriva-
tives, aminobenzamides
In recent years, deep eutectic solvents (DESs) have
emerged as promising green solvents. These are preferred
to conventional organic solvents because they are nonvola-
tile, nonflammable, nontoxic, biodegradable, inexpensive,
The isoindolone fragment forms part of the skeletal
framework of many synthetic or naturally occurring biolog-
ically active products.1–8 Isoindolo[2,1-a]quinazoline-5,11-
dione derivatives have been reported to exhibit various bio-
logical activities, including inhibition of tumor necrosis fac-
tor-α, which plays a major role in the treatment of rheuma-
toid arthritis, Crohn’s disease, and ulcerative colitis.9 Re-
ported methods for the synthesis of isoindolo[2,1-a]-
quinazoline derivatives include reactions catalyzed by ace-
tic acid,10,11 montmorillonite K10,9 β-cyclodextrin,12 Sac-
charomyces cerevisiae,13 CuO nanoparticles,14 iodine in an
ionic liquid,15,16 SnCl2·2H2O,17 or Fe in acetic acid.18 Pyrro-
lo[1,2-a]quinoxalines have been prepared by a Mannich
protocol,19,20 a 1,3-dipolar cycloaddition reaction strategy,21
a base-catalyzed approach,22 visible light induced photore-
dox catalysis,23 a modified Pictet–Spengler reaction cata-
lyzed by TsOH with benzotriazole as an additive,24 or intra-
molecular amidoalkylation–cyclization,25 and by phase-
transfer-catalyzed or trimethylsilyl cyanide catalyzed
routes for the synthesis of their Reissert analogues.26 Meth-
recyclable, and have excellent solvation properties.30–36
A
DES is usually composed of a mixture of a quaternary am-
monium salt and a hydrogen-bond donor. Several DESs
with choline chloride (ChCl) as the quaternary ammonium
salt component have been developed.
Here, we report an environmentally benign synthesis of
derivatives of 6,6a-dihydroisoindolo[2,1-a]quinazoline-
5,11-dione 3a–g, isoindolo[2,1-a]pyrrolo[2,1-c]quinoxalin-
10(14bH)-one 5a–f, and indolo[1,2-a]isoindolo[1,2-c]qui-
noxalin-11(15bH)-one (7a,b) in a deep eutectic solvent pre-
pared from p-toluenesulfonic acid and choline chloride
(Scheme 1).
The reaction between 2-formylbenzoic acid (1) and 2-
aminobenzamide (2a) in DES as the reaction medium was
studied under various conditions (Table 1). The reaction
failed at room temperature when ChCl–oxalic acid or ChCl–
malonic acid was used as the DES (Table 1, entries 1 and 5).
In these cases, heating to 80 °C for one hour was necessary
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

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R. V. Devi et al.
Letter
Synlett
lated product was highly pure, as evident from TLC analysis,
O
O
N
R1
and was identified as isoindolo[2,1-a]quinazoline (3a) on
R1
N
H
N
1
the basis of its H NMR spectrum, which was identical to
NH2
that reported.10 We obtained 3a in 95% yield.
2a–g
O
Table 2 Reactions of 2-Formylbenzoic Acid with 2-Aminobenzamides,
2-(1H-pyrrol-1-yl)anilines or 2-(1H-indol-1-yl)anilines in the Deep Eu-
tectic Solventa
3a–g
N
NH2
O
O
N
R1
R1
R2
N
N
H
COOH
N
4a–f
ChCl–TsOH
RT
O
NH2
N
CHO
R2
2
O
5a–f
R3
1
3
R3
N
N
NH2
NH2
N
N
N
R2
N
6a,b
COOH
4
ChCl–TsOH
RT
O
O
R2
CHO
7a,b
5
R3
1
Scheme 1
N
NH2 R3
for complete consumption of the starting materials (entries
4 and 8). The same reaction proceeded at room tempera-
ture within 15 minutes when a DES consisting of choline
chloride and TsOH was used (entry 9). This was therefore
established as the optimal protocol. The reaction mixture,
on dilution with a small amount of water, afforded a solid
product that could be isolated by simple filtration. The iso-
N
6
N
O
7
Entry
Substrate
Product
Time (h)
Yieldb (%)
1
2
2a; R1 = H
3a
3b
3c
3d
3e
3f
0.25
1
95c
88
87
84
80
81
88
90
85
90
88
80
82
90
92
Table 1 Screening of DESs
2b; R1 = Me
2c; R1 = Ph
2d; R1 = Bn
2e; R1 = 4-Tol
O
3
1
O
NH
4
1
COOH
NH2
DES
RT, –80 °C
N
5
1
+
NH2
CHO
6
2f; R1 = 4-MeOC6H4
2g; R1 = 3-Tol
4a; R2 = H
1
O
1
2a
3a
7
3g
5a
5b
5c
5d
5e
5f
1
8
0.75
3.5
0.33
0.42
5
Entry
DES
Time (h)
Temp (°C)
Yield (%)
9
4b; R2 = 5-CO2H
4c; R2 = 5-OMe
4d; R2 = 5-OBn
4e; R2 = 4-ClCC6H4
4f; R2 = 5-ClCC6H4
6a; R3 = H
1
2
3
4
5
6
7
8
9
ChCl–oxalic acid
12
10
8
r.t.
40
60
80
r.t.
40
60
80
r.t.
no reaction
10
11
12
13
14
15
traces
60
1
85
5
ChCl–malonic acid
ChCl–TsOH
12
10
8
no reaction
7a
7b
2
traces
55
6b; R2 = Br
2
a Reaction conditions: 2-formylbenzoic acid (1; 1 mmol), amine 2, 4, or 6 (1
mmol), ChCl–TosOH DES (1.5 g), RT.
1
90
b Isolated yield after crystallization.
c This compound required no crystallization.
0.25
95
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

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R. V. Devi et al.
Letter
Synlett
Next, we evaluated the scope of the protocol by carrying
out the reactions of 2-formylbenzoic acid (1) with various
2-aminobenzamide derivatives 2 (Table 2, entries 1–7). A
wide range of 2-aminobenzamide derivatives 2 gave the
corresponding isoindolo[2,1-a]quinazolines 3a–g within
one hour. All the synthesized products (apart from 3a) were
crystallized from ethanol to remove traces of impurities.
We were also able to extend the scope of this protocol to
the synthesis of isoindolo[2,1-a]pyrrolo[2,1-c]quinoxalin-
10(14bH)-ones 5a–f by the reaction of 2-formylbenzoic
acid (1) with 2-(1H-pyrrol-1-yl)aniline derivatives 4. The
protocol tolerated 2-(1H-pyrrol-1-yl)aniline derivatives 4
with electron-donating or electron-withdrawing groups
(entries 9–13). The reaction between 2-formylbenzoic acid
and 2-(1H-pyrrol-1-yl)aniline derivatives having electron-
withdrawing groups (entries 9, 12, and 13) took longer for
completion of the reaction. The same reaction strategy was
successfully applied to the synthesis of indolo[1,2-a]iso-
indolo[1,2-c]quinoxalin-11(15bH)-one derivatives 7a,b
through the reaction of 2-formylbenzoic acid (1) with 2-
(1H-indol-1-yl)aniline derivatives 6a,b (entries 14 and 15).
A significant feature of this protocol lies in the recy-
clability of DESs. The DES used in the model reaction of 2-
formylbenzoic acid (1) with 2-aminobenzamide (2a) was
recovered as described in the Supporting Information and
reused in two further runs of the reaction to give product
3a in yields of 91% and 88% from the second and third cycle,
respectively (Table 3).
References and Notes
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Table 3 Reusability of the DES
Entry
Reaction cycle
Yielda (%)
1
2
3
first (fresh)
second
third
95
91
88
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53, 14451.
In conclusion, we have developed a highly efficient, one-
pot, green protocol for the synthesis of derivatives of 6,6a-
dihydroisoindolo[2,1-a]quinazoline-5,11-dione, isoindolo-
[2,1-a]pyrrolo[2,1-c]quinoxalin-10(14bH)-one, and indolo-
[1,2-a]isoindolo[1,2-c]quinoxalin-11(15bH)-one.37
(24) Verma, A. K.; Jha, R. R.; Sankar, V. K.; Aggarwal, T.; Singh, R. P.;
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Acknowledgment
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R.V.D. thanks the Jawaharlal Nehru Memorial Fund (JNMF), New Del-
hi, and A.M.G. thanks the University Grants Commission (UGC), New
Delhi, for providing their research fellowships.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

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(34) Tang, B.; Row, K. H. Monatsh. Chem. 2013, 144, 1427.
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(37) 6,6a-Dihydroisoindolo[2,1-a]quinazoline-5,11-diones 3a–g,
Isoindolo[2,1-a]pyrrolo[2,1-c]quinoxalin-10(14bH)-ones 5a–f,
and Indolo[1,2-a]isoindolo[1,2-c]quinoxalin-11(15bH)-ones
7a,b; General Procedure
stirred at r.t. until the starting materials were completely con-
sumed (TLC). The reaction mass was then diluted with H2O (5
mL), and the desired product, obtained as a precipitate, was iso-
lated by filtration and crystallized from the appropriate solvent.
The filtrate was evaporated under vacuum at 70 °C for 2 h, and
the residual DES was reused in further reaction cycles.
6,6a-Dihydroisoindolo[2,1-a]quinazoline-5,11-dione (3a)
White solid; yield: 237 mg (95%); 1H NMR (500 MHz, DMSO-
d6): δ = 9.406 (s, 1 H), 8.089 (d, J = 7.5 Hz, 1 H), 7.983 (d, J = 7 Hz,
1 H), 7.898 (d, J = 7 Hz, 2 H), 7.801 (t, J = 7 Hz, 1 H), 7.724–7.688
(m, 2 H), 7.361 (t, J = 7 Hz, 1 H), 6.526 (s, 1 H).
To a mixture of 2-formylbenzoic acid (1; 1 mmol) and the
appropriate amine 2, 4, or 6 (1 mmol) was added the DES (1.5
g), prepared from ChCl and TsOH.31 The resulting mixture was
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D