Synthesis of different isoindolone embedded heterocycles with phenolic subunits from a common intermediate, 3-(2′-hydroxyaroyl)-2,3- dihydroisoindol-1-ones

Article abstract of DOI:10.1016/j.tetlet.2014.06.064

A series of biologically important isoindolone embedded heterocycles such as tetracyclic 2,4-diamino-5-aryl-10-oxo-10H-1,10a-diazaindeno[2,1-a]indene-3- carbonitriles and tricyclic 1-aryl-3,5-dioxo-1H-imidazo-[3,4-b]isoindoles have been synthesized from an easily derived common intermediate, 3-(2′-hydroxyaroyl)-2,3-dihydroisoindol-1-ones. The significant advantages of the present methodologies are the use of simple and easily available starting materials and reagents, operational simplicity, and good yields of the products with high atom-economy.

Full text of DOI:10.1016/j.tetlet.2014.06.064

Accepted Manuscript
Synthesis of different isoindolone embedded heterocycles with phenolic subu-
nits from a common intermediate, 3-(2′-hydroxyaroyl)-2, 3-dihydroisoindol-1-
ones
Ashis Kundu, Animesh Pramanik
PII:
S0040-4039(14)01055-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.06.064
TETL 44788
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 May 2014
13 June 2014
14 June 2014
Please cite this article as: Kundu, A., Pramanik, A., Synthesis of different isoindolone embedded heterocycles with
phenolic subunits from a common intermediate, 3-(2′-hydroxyaroyl)-2, 3-dihydroisoindol-1-ones, Tetrahedron
Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.06.064
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Synthesis of different isoindolone embedded heterocycles with
phenolic subunits from a common intermediate, 3-(2′-
hydroxyaroyl)-2, 3-dihydroisoindol-1-ones
Ashis Kundu and Animesh Pramanik*
Department of Chemistry, University of Calcutta, 92, A. P. C. Road, Kolkata-700 009,
India; Fax: +91-33-2351-9755; Tel: +91-33-2484-1647.
E-mail: animesh_in2001@yahoo.co.in
ABSTRACT
A series of biologically important isoindolone embedded heterocycles such as tetracyclic 2,4-
diamino-5-aryl-10-oxo-10H-1,10a-diazaindeno[2,1-a]indene-3-carbonitriles and tricyclic 1-aryl-
3,5-dioxo-1H-imidazo-[3,4-b]isoindoles have been synthesized from an easily derived common
intermediate, 3-(2′-hydroxyaroyl)-2,3-dihydroisoindol-1-ones. The significant advantages of the
present methodologies are the use of simple and easily available starting materials and reagents,
operational simplicity and good yields of the products with high atom-economy.
Keywords: Fused isoindolones, Ninhydrin adducts, Microwave heating, Condensation reactions,
Heterocycles.
Isoindole and its derivatives are used as scaffolds for synthesis of diverse range of
biologically active molecules.1,2 Among these the isoindolone fused tetracyclic heterocycle A
1

possesses intrinsic anticancer activity3 and heterocycle B shows high sub-nanomolar affinity for
the melatonin binding site MT34 (Fig. 1). Moreover isoindolone fused heterocycle C shows the
ability to bind to the nNK1 receptor5 (Fig. 1). Heterocycle C can also be employed as a precursor
for the synthesis of NorA efflux pump inhibitors.6 Recently medicinal research on these
tetracyclic heterocycles (A-C) reveals that they have antibacterial and antifungal activity.7
Further studies also show that they have antiproliferative effects against HT-29 and L1210 cell
lines.8
O
NEt2
OH
O
N
N
O
N
H
O
O
A
B
O
O
N
N
N
O
C
Figure 1. Biologically important heterocycles A-C
Imidazolone based heterocycles are prevalent in many natural products and also play an
important role in various biochemical processes.9 Generally they are used as building blocks in
the development of various drugs such as COX-2 inhibitors,10a anti-inflammatory,10b
anticancer,10c,d cardioactive agents10e and angiotensin II receptor antagonists10f. The use of
imidazoisoindolone based orally active drugs for the treatment of respiratory syncytial virus
(RSV) has been explored extensively.11 Therefore, simple and efficient synthesis of isoindolone
fused imidazolones and other heterocycles similar to tetracyclic A-C (Fig. 1), substituted with
different functional groups is important for further biological evaluation. As part of our research
2

interest for the synthesis of bio-active compounds from ninhydrin,12 we wish to report herein
some general and efficient methodologies for the synthesis of isoindolone embedded
heterocycles with diverse functional groups from easily available starting materials.
Recently we have reported that refluxing a mixture of ninhydrin adducts of phenols 1 and
ammonium acetate in acetic acid produces 3-(2′-hydroxyaroyl)-2,3-dihydroisoindol-1-ones 2 in
good yield (Scheme 1).12a Further it has been shown that the compound 2 can be utilized
successfully in the synthesis of a series of novel spiro isoindoles.12a This result incited us for
exploring the potential of adduct 2 as an intermediate in the synthesis of various isoindolone
embedded heterocycles. Several examples show that both the active methylene group and cyano
group of malononitrile (3) can participate in various reactions to form variety of addition
products and heterocyclic compounds.13 Therefore, considering the presence of electrophilic and
nucleophilic functionalities in adduct 2 we choose malononitrile as a potential reactant for
condensation with 2. Interestingly when a mixture of compound 2d (R = p-CH3 with respect to
phenolic –OH) and malononitrile was refluxed in ethanol in presence of base triethylamine, a
new tetracyclic compound 2,4-diamino-5-aryl-10-oxo-10H-1,10a-diazaindeno[2,1-a]indene-3-
carbonitrile 4d was formed within 3 h (Scheme 2).14 With the result in hand we then attempted to
optimize the reaction condition to achieve maximum yield of the product. The reaction between
compound 2d and malononitrile 3 was chosen for the survey of the reaction. When the reaction
was carried out under solvent-free condition without using any catalyst, no product was formed
on heating (Table 1, entry 1). Subsequently the reaction was carried out in water with the base
triethylamine, but still no desired product was formed (Table 1, entry 2). Probably the low
solubility of 2d in water hindered the reaction. However, refluxing a mixture of 2d (1.0 mmol)
and malononitrile (3.0 mmol) in ethanol (5.0 mL) in presence of triethylamine (0.5 equiv)
3

produced the desired product 4d in good yield (Table 1, entry 3). After that we varied the amount
of triethylamine in the reaction (Table 1, entry 4 and 5) and observed that minimum 0.5 equiv of
triethylamine was required to get maximum yield of the product 4d. Then we employed various
other solvents like MeOH, CH3CN and DMF (Table 1, entries 6, 7 and 8), among which ethanol
appeared to be the best solvent. We also used various organic bases like piperidine, pyridine,
pyrrolidine and triethanolamine (Table 1, entries 9-12) but triethylamine produced the best result
as a catalyst of the reaction (Table 1, entry 3). Various inorganic bases were also used in the
reaction but it was observed that in presence of strong bases such as KOH and NaOH, the adduct
2d totally decomposed without producing 4d (Table 1, entries 13 and 14). Mild inorganic bases
such as Cs2CO3 and K2CO3 produced 4d in very low yield, 12-15% (Table 1, entries 15 and 16).
O
O
NH
OH
O
NH4OAC
R
AcOH, reflux
HO
O
OH
R
1
2
Scheme 1. Synthesis of 3-(2’-hydroxyaroyl)-2,3-dihydroisoindol-1-ones 2 from adducts 1.
O
O
N
NH2
N
NH
CN
CN
Et3N
CN
+
HO
O
EtOH
NH2
Reflux, 3 h
OH
R
R
3
2a-m
4a-m
4

Scheme 2. Synthesis of 2,4-diamino-5-aryl-10-oxo-10H-1,10a-diazaindeno[2,1-a]indene-3-
carbonitriles 4 from intermediates 2.
Table 1 Optimization of reaction condition for the synthesis of 4d from intermediate 2da
Amount of
catalyst load
(equiv)
Entry
Catalyst
Solvent
(5.0 ml)
−
Time (h)
Yield (%)b
1
2
−
−
Et3N
12
12
3
−
0.5
0.5
0.2
1.0
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
H2O
−
3
Et3N
EtOH
EtOH
EtOH
MeOH
CH3CN
DMF
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
75
28
75
62
60
57
67
59
69
36
4
Et3N
3
5
Et3N
3
6
Et3N
3
7
Et3N
3
8
Et3N
3
9
piperidine
pyridine
pyrrolidine
triethanolamine
KOH
3
10
11
12
13
14
15
16
3
3
3
c
−
3
c
−
NaOH
3
Cs2CO3
K2CO3
3
15
12
3
a
1.0 mmol of 2d and 3.0 mmol of malononitrile were used in all reactions.
b isolated yield of 4d.
c decomposition of the adduct 2d occurred.
After optimization of the reaction condition, we assessed the scope and generality of the
reaction by employing various adducts 2 with a variety of electron donating and electron
5

withdrawing substituents in the phenolic group. The results are summarized in Table 2 which
shows that it is a very general reaction with high yields of products 4. All the products were fully
1
characterized by H and 13C NMR and elemental analyses. Further, elucidation of the crystal
structure of compound 4l confirmed the formation of isoindolone fused tetracyclic heterocycles
substituted with consecutive donor(-NH2)-acceptor(-CN)-donor(-NH2) and various phenolic
16
groups (Fig. S1).15 On the basis of previous reports
a plausible mechanism for the formation
of compound 4 is depicted in Scheme 3. The process comprises a cascade of reactions with an
initial base catalyzed Knoevenagel condensation between compound 2 and malononitrile to
furnish intermediate 5. Subsequently another molecule of malononitrile attacks the nitrile group
of intermediate 5 to produce intermediate 6. Then intermediate 6 undergoes tandem cyclization
followed by tautomerization and aromatization to furnish the final compound 4. It was not
possible to isolate any of the intermediates under the reaction conditions.
Table 2 Synthesis of 2,4-diamino-5-aryl-10-oxo-10H-1,10a-diazaindeno[2,1-a]indene-3-
carbonitriles 4 from intermediates 2
Time
(h)
Melting
Entry
Adduct (2)a
Product (4)
Yield (%)b Point (oC)
O
O
N
NH2
NH
N
1
3
78
> 320
O
CN
HO
NH2
OH
2a
4a
6

O
O
2
N
NH2
NH
N
3
73
> 320
O
CN
HO
NH2
OH
4b
2b
O
O
N
NH2
N
NH
3
71
> 320
3
CN
O
HO
NH2
OH
2c
4c
O
O
N
NH2
NH
N
O
CN
HO
NH2
4
3
75
> 320
OH
2d
4d
O
O
N
NH2
N
NH
5
3
70
> 320
CN
HO
O
NH2
OH
Cl
Cl
4e
2e
7

O
O
N
NH2
NH
N
6
3
72
> 320
CN
O
HO
NH2
Cl
OH
Cl
2f
4f
O
O
O
O
O
O
N
NH2
N
3
75
> 320
NH
7
8
9
CN
HO
HO
HO
O
NH2
F
OH
F
2g
4g
N
NH2
N
NH
3
73
> 320
CN
O
NH2
Br
OH
Br
2h
4h
N
NH2
NH
N
3
75
> 320
O
CN
Ph
NH2
OH
Ph
2i
4i
8

O
O
N
NH2
N
NH
10
3
71
> 320
CN
HO
O
NH2
H3CO
OH
OCH3
4j
2j
O
O
N
NH
2
N
NH
11
3
74
> 320
CN
HO
O
NH
2
H3CO2C
OH
CO CH
2
2k
3
4k
O
O
N
NH2
NH
N
12
3
73
> 320
CN
O
HO
Cl
NH2
OH
Cl
2l
4l
O
O
N
NH2
N
NH
13
3
70
> 320
CN
HO
O
NH2
OH
4m
2m
9

a unpurified compounds 2 were used in all reactions.12a
b isolated yields w. r. t. adducts 1.
O
O
O
N H
NH
CN
NH
N
N
CN
CN
HO
HO
HO
CN
CN
O
Et3N
CN
HN
N
R
R
R
2
5
6
O
O
N
NH
CN
N
NH2
CN
N
N
H
HO
HO
H
NH
NH2
R
R
4
7
Scheme 3. Plausible mechanism for the formation of compounds 4
Microwave assisted organic synthesis (MAOS) under solvent-free condition is a popular
methodology which serves the purpose of green chemistry.17 Therefore after successful synthesis
of compounds 4a-m we attempted to carry out another condensation reaction by heating a solid
mixture of compound 2 and urea (8) under microwave irradiation (Scheme 4). Interestingly a
series of yellow solid products were isolated from these reactions in good yield within 20-35
min. The products were characterized by 1H and 13C NMR spectroscopy and found to be 1-aryl-
3,5-dioxo-1H-imidazo-[3,4-b]isoindoles 9a-o, the condensation products of intermediates 2 and
10

urea (Scheme 4, Table 3).14 Determination of the X-ray crystal structure further confirmed the
formation of product 9d (Fig. S2).15
O
O
O
N
N H
O
NH
Solid state
+
MW irradiation
O
H2N
NH2
OH
R
OH
R
9a-o
8
2a-o
Scheme 4. Synthesis of 1-aryl-3,5-dioxo-1H-imidazo-[3,4-b]isoindoles 9 from intermediates 2
Table 3 Synthesis of 1-aryl-3,5-dioxo-1H-imidazo-[3,4-b]isoindoles 9 from intermediates 2
Literature
m.p12i /
Entry
Adduct (2)a
Product
Time
(min)
Yield
(%)b
(9)
Observed mp
(ºC)
O
O
N
NH
1
20
75
305-307
/302-304
2a
OH
9a
254-256
11

O
2
20
77
/252-253
2b
O
N
NH
OH
9b
O
O
N
221-222
/219-221
NH
3
20
71
2c
OH
9c
O
O
N
289-291
/287-288
NH
4
20
73
2d
OH
9d
O
O
N
274-275
/270-272
NH
5
25
75
2e
OH
Cl
9e
12

O
O
N
308-310
/303-305
NH
6
25
69
2f
OH
Cl
9f
O
O
N
NH
>320
7
25
70
2g
OH
F
9g
O
O
N
306-307
/302-304
NH
8
20
68
2h
OH
Br
9h
O
O
N
NH
9
20
67
310-311
2i
OH
Ph
9i
13

O
298-300
/295-297
O
N
10
35
64
2j
NH
OH
H3CO
9j
O
O
N
314-316
/311-313
NH
11
30
67
2k
OH
H3CO2C
9k
O
316-318
/313-315
O
N
30
65
NH
12
2l
OH
Cl
9l
O
O
O
N
NH
13
30
64
295-297
NH
O
OH
OH
2n
9n
14

O
O
O
NH
N
NH
>320
14
35
67
O
Cl
OH
OH
Cl
Cl
Cl
2o
9o
a unpurified compounds 2 were used in all reactions.12a
b isolated yields w. r. t. adducts 1.
Previously the series of compounds 9a-o were also synthesized in our laboratory by
refluxing the ninhydrin adducts of phenols 1 and urea in acetic acid for 2.5-8 h.12i The present
method produces compounds 9 in comparable yield to that of the previous method12i within a
shorter period of time (~ 2.0 h) in two steps starting from ninhydrin adducts of phenols 1 via
intermediate 2. Further isolation and charaterization of intermediate 212a and direct condensation
of 2 with urea under solvent-free condition provide insights about the mechanistic pathway for
the formation of compound 9, which was not possible previously. Compounds 9 show
interesting photophysical property and are being used as fluorescence marker in various
biochemical and photochemical processes.12i, 18
In conclusion, we have successfully developed some simple and efficient methodologies
for the synthesis of potentially bioactive isoindolone embedded heterocycles such as tetracyclic
2,4-diamino-5-aryl-10-oxo-10H-1,10a-diazaindeno[2,1-a]indene-3-carbonitriles and tricyclic
1-aryl-3,5-dioxo-1H-imidazo-[3,4-b]isoindoles from an easily derived common intermediate.
The microwave assisted synthesis of tricyclic heterocycles through the condensation of this
intermediate with urea under solvent-free condition is environmentally friendly. The present
15

methodologies will be useful to organic and pharmaceutical chemists due to simple and easily
available starting materials and reagents, good yields of the products, high atom-economy and
operational simplicity.
Acknowledgements
A. K. thanks the University Grant Commission (UGC) for offering Senior Research Fellowship
(SRF). The financial assistance of CSIR, New Delhi is gratefully acknowledged [Major Research
Project, No. 02(0007)/11/EMR-II]. Crystallography was performed at the DST- FIST, India-
funded single crystal diffractometer facility at the Department of Chemistry, University of
Calcutta.
Supplementary data
Supplementary data associated with this article can be found, in the online version, at
http://dx.doi.org/
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14. Typical procedure for the preparation of compound 4d from adduct 2d: A mixture
of crude adduct 2d (obtained from 1.0 mmol of ninhydrin adduct of p-cresol, 1d)12a,
malononitrile (3.0 mmol w. r. t. 1d) and triethylamine (0.5 mmol w. r. t. 1d) in ethanol (5
18

mL) was refluxed for 3 h. The yellow solid was precipitated out from the reaction
mixture on cooling. The solid was filtered and washed with cold alcohol to get the pure
compound 4d.
2,4-diamino-5-(2′-hydroxy-5′-methylphenyl)-10-oxo-10H-1,10a-diazaindeno[2,1-a]
indene-3-carbonitrile (4d): Yellow solid, mp > 320°C; IR (KBr): 1643, 2206, 3341 cm-1;
1H NMR (300 MHz, DMSO-d6) δ: 9.78 (s, 1H), 7.73 (d, J =7.5 Hz, 1H), 7.50 (t, J =7.5
Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 7.21-7.16 (m, 2H), 6.99-6.97 (m, 2H), 6.81 (s, 2H),
5.83 (s, 2H), 2.27 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ: 161.2, 161.0, 153.2, 153.1,
149.1, 134.9, 134.5, 131.8, 131.6, 131.5, 128.9, 128.6, 128.1, 125.7, 121.2, 120.7, 118.3,
116.8, 115.3, 104.0, 71.0, 20.4; Anal. calcd for C22H15N5O2: C, 69.28; H, 3.96; N, 18.36
% found C, 69.12; H, 3.89; N, 18.28 %.
2,4-diamino-5-(3′-chloro-2′-hydroxyphenyl)-10-oxo-10H-1,10a-diazaindeno[2,1-a]
indene-3-carbonitrile (4e): Yellow solid, mp > 320°C; IR (KBr): 1634, 2202, 3396 cm-1;
1H NMR (300 MHz, DMSO-d6) δ: 9.72 (s, 1H), 7.67 (d, J =7.5 Hz, 1H), 7.51-7.42 (m,
2H), 7.35-7.24 (m, 2H), 6.97 (t, J =7.8 Hz, 1H), 6.83 (d, J =7.8 Hz, 1H), 6.76 (s, 2H),
5.67 (s, 2H); 13C NMR (75 MHz, DMSO-d6) δ: 161.2, 161.0, 152.8, 151.2, 149.2, 135.1,
134.2, 131.8, 131.4, 130.1, 129.5, 128.4, 125.8, 122.2, 121.4, 121.1, 120.7, 116.8, 113.4,
103.7, 71.0; Anal. calcd for C21H12N5O2Cl: C, 62.77; H, 3.01; N, 17.43 % found C,
62.59; H, 2.94; N, 17.34 %.
Typical procedure for the preparation of compound 9g from adduct 2g: A solid
mixture of crude adduct 2g (obtained from 1.0 mmol of ninhydrin adduct of p-fluoro-
phenol, 1g)12a and urea (5.0 mmol w. r. t. 1g) was heated under MW irradiation at 150
o
watt (temp. 123 C) for 25 min in an open vial (a BPL oven, Model No. BMO 800 TS
19

was used). After the completion of the reaction (monitored by TLC) cold water was
added to the reaction mixture, extracted with ethylacetate and concentrated under reduced
pressure. The crude mass obtained was purified through column chromatography
(EtOAc/Hexane) to get the pure compound 9g.
1-(5′-fluoro-2′-hydroxyphenyl)-3,5-dioxo-1H-imidazo[3,4-b]isoindole (9g): Yellow solid,
mp > 320°C; IR (KBr): 1670, 1750, 3274 cm-1; 1H NMR (300 MHz, DMSO-d6) δ: 10.90
(bs, 1H), 10.45 (bs, 1H), 7.81 (d, J=7.5 Hz, 1H), 7.68 (t, J=7.5 Hz, 1H), 7.44-7.39 (m,
2H), 7.31-7.17 (m, 2H), 7.07-7.02 (m, 1H); 13C NMR (75 MHz, DMSO-d6, F coupled
13C) δ: 160.7, 157.0, 153.9, 151.9, 147.7, 134.6, 132.3, 131.2, 127.8, 125.7, 122.9, 119.4,
118.3, 117.9, 117.8, 115.9, 115.8, 115.6; Anal. calcd for C16H9N2O3F: C, 64.87; H, 3.06;
N, 9.46 % found C, 64.69; H, 2.98; N, 9.35 %.
1-(3′,5′-dichloro-2′-hydroxyphenyl)-3,5-dioxo-1H-imidazo[3,4-b]isoindole (9o): Yellow
solid, mp > 320 °C; IR (KBr): 1690, 1761, 3279 cm-1; 1H NMR (300 MHz, DMSO-d6) δ:
10.93 (bs, 1H), 10.46 (bs, 1H), 7.83 (d, J=7.5 Hz, 1H), 7.71-7.67 (m, 2H), 7.56 (s, 1H),
7.51-7.46 (m, 1H), 7.30 (d, J=7.8 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ: 160.7,
150.2, 147.6, 134.9, 131.9, 131.2, 130.8, 128.5, 128.1, 125.8, 124.0, 123.5, 122.5, 119.3,
118.8, 118.0; Anal. calcd for C16H8N2O3Cl2: C, 55.36; H, 2.32; N, 8.07 % found C,
55.19; H, 2.25; N, 7.98 %.
15. Crystallographic data for the structure 4l and 9d in this Letter have been deposited with
Cambridge Crystallographic Data Centre as supplementary publication no. CCDC
962749 and CCDC 972301, respectively. Copies of the data can be obtained, free of
charge via the website www.ccdc.cam.ac.uk/data_request/cif.
20

16. (a) Olyaei, A.; Vaziri, M.; Razeghi, R. Tetrahedron Lett. 2013, 54, 1963; (b) Osyanin, V.
A.; Osipov, D. V.; Klimochkin, Y. N. Tetrahedron 2012, 68, 5612; (c) Evdokimov, N.
M.; Kireev, A. S.; Yakovenko, A. A.; Antipin, M. Y.; Magedova, I. V.; Kornienko, A.
Tetrahedron Lett. 2006, 47, 9309.
17. (a) Polshettiwar, V.; Varma, R. S. Acc. Chem. Res. 2008, 41, 629; (b) Roberts, B. A.;
Strauss, C. R. Acc. Chem. Res. 2005, 38, 653.
18. (a) Koley, P.; Pramanik, A. Adv. Funct. Mater. 2011, 21, 4126; (b) Ray, D.; Pramanik,
A.; Guchhait, N. RSC Adv. 2014, 4, 13256; (c) Ray, D.; Pramanik, A.; Guchhait, N. J.
Photochem. Photobiol. A: Chem. 2014, 274, 33.
21

Graphical Abstract
Synthesis of different isoindolone embedded heterocycles with
phenolic subunits from a common intermediate, 3-(2′-
hydroxyaroyl)-2, 3-dihydroisoindol-1-ones
Ashis Kundu and Animesh Pramanik*
O
O
O
O
N
NH2
CN
N
NH
N
Urea
Solidstate
NH
CH2(CN)2
O
HO
MWirradiation
20-35 min
Et3N, EtOH
Reflux, 3h
NH2
OH
R
OH
R
R
13 examples
70 -75%
14 examples
64 -77%
22