Facile synthesis of 3H,3′H-spiro[benzofuran-2,1′-isoindole]-3, 3′-diones using monobromomalononitrile (MBM) as an efficient organo-brominating agent

Article abstract of DOI:10.1016/j.tetlet.2014.04.027

An efficient methodology for the synthesis of 3H,3′H- spiro[benzofuran-2,1′-isoindole]-3,3′-diones has been developed where monobromomalononitrile (MBM) has been employed as a non-hazardous brominating agent under ambient reaction condition. The intrinsic advantages of the methodology are the utilization of simple and easily available starting materials and non-toxic reagents, operational simplicity, and good yields of the products with high atom-economy.

Full text of DOI:10.1016/j.tetlet.2014.04.027

Accepted Manuscript
Facile synthesis of 3H, 3′ H-spiro[benzofuran-2,1′-isoindole]-3, 3′-diones using
monobromomalononitrile (MBM) as an efficient organo-brominating agent
Ashis Kundu, Sudipta Pathak, Kamalesh Debnath, Animesh Pramanik
PII:
S0040-4039(14)00626-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.04.027
TETL 44489
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 March 2014
9 April 2014
9 April 2014
Please cite this article as: Kundu, A., Pathak, S., Debnath, K., Pramanik, A., Facile synthesis of 3H, 3′ H-
spiro[benzofuran-2,1′-isoindole]-3, 3′-diones using monobromomalononitrile (MBM) as an efficient organo-
brominating agent, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.04.027
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Facile synthesis of 3H, 3′H-spiro[benzofuran-2,1′-isoindole]-3,
3′-diones using monobromomalononitrile (MBM) as an efficient
organo-brominating agent
Ashis Kundu, Sudipta Pathak, Kamalesh Debnath 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
An efficient methodology for the synthesis of 3H,3′H-spiro[benzofuran-2,1′-isoindole]-3,3′-
diones has been developed where monobromomalononitrile (MBM) has been employed as a
non-hazardous brominating agent under ambient reaction condition. The intrinsic advantages of
the methodology are the utilization of simple and easily available starting materials and non-
toxic reagents, operational simplicity and good yields of the products with high atom-economy.
Keywords: Monobromomalononitrile, Spiroisoindoles, Bromination, Green chemistry,
Operational simplicity
Heterocyclic compounds embedded with isoindole moiety are present in numerous
natural products and pharmaceutical leads.1 Diverse biological activities of isoindole derivatives
such as anti-inflammatory,2 anticancer,3 anti-tuberculosis,4 HIV-1 integrase inhibitor5 and
heparanase inhibitor6 activities have attracted considerable attention over the years. As a
consequence, a number of methods have been developed for the synthesis of various isoindole
1

derivatives.7 Similarly benzofuran moieties are also present as key structural subunits in many
naturally occurring bioactive molecules.8 They also act as building blocks in the synthesis of
various natural products.8 Benzofuran heterocycles show diverse range of pharmacological
properties such as antibacterial,9 antimicrobial,10 antitumor11 and antifungal12 activities. They are
also known to act as estrogen receptor (ER) ligands,13 H3 receptor antagonists,14 selective ligands
for the dopamine D3 receptor subtype,15 metalloproteinase-13 inhibitors16 and modulator of
calcium level.17 While isoindole and benzofuran derivatives have attracted significant attention
over the years, the synthesis of spiroheterocyclic compounds containing both isoindole and
benzofuran motifs has not been the subject of much research till now.18 Therefore, development
of new and efficient methodology for the synthesis of this type of spiroheterocycles is well
deserved which may show important biological and structural property.
Monobromomalononitrile (MBM) is generally used in the synthesis of various
heterocyclic compounds19 where MBM mainly participates in addition reactions with carbonyl
groups,19a-c α,β-unsaturated double bonds,19a–c and isolated double bonds19d-f . Very recently we
have shown that MBM can also act as an efficient and selective brominating agent towards
active methylene compounds and enamines.20 In the present paper the potential of MBM as a
brominating agent in the synthesis of spiroheterocyclic compounds has been explored. As a part
of our ongoing research for the synthesis of bio-active compounds from ninhydrin,21 we wish to
report herein a general and efficient methodology for the synthesis of 3H,3′H-spiro[benzofuran-
2,1′-isoindole]-3,3′-diones using MBM as an organo-brominating agent under ambient reaction
condition.
As a part of our present investigation initially we refluxed several mixtures of ninhydrin
adducts of phenols 122 and ammonium acetate in acetic acid. Interestingly from these reactions
2

we obtained a new class of compounds 3-(2′-hydroxybenzoyl)-2,3-dihydroisoindol-1-ones 2 in
high yields within 1-2 h (Scheme 1, Table 1).23 Most of the compounds 2 were found to
decompose on silica gel during purification by column chromatography. However, we were
successful in purifying some of the compounds (2d, 2f, 2l and 2m) for characterization by IR, 1H
13
NMR, C NMR and other analyses. The determination of X-ray crystal structure of compound
2d (Fig. 1)24 confirms the product formation. It shows that the class of compound 2 possesses
electrophilic and nucleophilic functionalities such as carbonyl, amide nitrogen and phenolic
hydroxyl group in suitable disposition for synthesis of isoindole embedded heterocycles through
further reactions.
O
O
NH
OH
NH4OAc
O
R
AcOH, Reflux
HO
O
OH
R
1a-o
2a-o
Scheme 1. Synthesis of 3-(2’-hydroxybenzoyl)-2,3-dihydroisoindol-1-one 2 from adduct 1.
3

O1
C8
C6
C7
C5
N1
O2
C9
C2
C4
C1
C3
C10
O3
C11
C15
C12
C13
C14
C16
Figure 1. ORTEP diagram of the X-ray crystal structure of compound 2d with the atomic
numbering scheme (CCDC No. 962748).
Table 1 Synthesis of 3-(2’-hydroxybenzoyl)-2,3-dihydroisoindol-1-ones 2 from adducts 1
HO
R
Entry
1
Product (2)a
Time (h)
1
HO
2a
HO
CH3
2
3
1
1
2b
2c
HO
CH3
HO
4
1
2d
CH3
4

HO
Cl
5
6
1.5
1.5
2e
2f
HO
Cl
HO
7
8
9
1.5
1.5
1.5
2g
2h
2i
F
HO
Br
HO
Ph
HO
10
1
2j
OCH3
HO
11
12
1.5
1.5
2k
2l
CO2CH3
HO
CH3
Cl
HO
13
14
1.5
1.5
2m
2n
HO
5

HO
Cl
Cl
15
2
2o
a Products 2 were not purified. The isolated crude masses of 2 were used for further reactions.
On the basis of previous reports21a-e, 22e a plausible mechanism for the formation of
compound 2 has been proposed, which is depicted in Scheme 2. In acidic medium, the
protonation of carbonyl oxygen of the bicyclo[3.3.0]octano system 1 initiates the breaking of the
central C–C bond to form an eight-membered lactone intermediate 3. Then intermediate 3
tautomerizes to intermediate 4, which subsequently condenses with ammonia to produce the
intermediate 5. Then the amine form of 5 i.e. the intermediate 6 undergoes intramolecular
nucleophilic attack by the amino group to the lactone carbonyl to form intermediate 7 which
finally tautomerizes to compound 2.
H+
O
OH
O
HO
OH
OH
R
R
R
O
H
O
O
O
O
1
O
3
4
NH3
O
O
HN
OH
H
H2N
OH
NH
NH
R
R
O
OH
O
O
O
O
OH
OH
R
R
6
5
7
2
Scheme 2. Plausible mechanism for the formation of compound 2
In our initial study, we attempted to alkylate the nitrogen of 2d using MBM (9) in DMF
medium for different synthetic purposes. Simple stirring of a mixture of 2d and MBM (1:1.2
6

mole) in DMF for 12 h at room temperature gives rise to the formation of a new compound with
considerable yield (45%) along with starting material (Table 2, entry 1). The structural
assignment of the isolated product with IR, 1H NMR, 13C NMR and elemental analysis shows the
formation of a new compound 5-methyl-3H,3′H-spiro[benzofuran-2,1′-isoindole]-3,3′-dione 8d
other than the N-alkylated product of 2d (Scheme 3). The determination of X-ray crystal
structure further confirms the formation of product 8d unambiguously (Fig. 2).24 It was obvious
that, instead of N-alkylation, MBM was working as a brominating agent in this reaction leading
to the formation of spiroheterocyclic compound 8d. Next, we tried to carry out the reaction with
other brominating agents such as NBS, Br2 and 1,3-dibromo-5,5-dimethyl hydantoin in place of
MBM under similar reaction conditions (Table 2, entries 2-4). However, in all the reactions
mixture of products was obtained along with product 8d due to bromination of the aromatic ring
of phenolic group. The formation of only product 8d in case of MBM suggests that it cannot
brominate aromatic ring. In order to maximize the yield of the product with MBM, the reaction
was carried out with various organo-bases such as Et3N, pyrrolidine, piperidine and pyridine
(Table 2, entries 5-8). Though the yield of the product was increased, still it was less than
satisfactory (51-58%). This result incited us for employing several inorganic bases such as
NaOH, Na2CO3, MgCO3, K2CO3, and Cs2CO3 (Table 2, entries 9-13). The formation of product
did not take place in NaOH solution as MBM was found to decompose in strong alkaline
solution (Table 2, entry 9). But, the yield of the product 8d was enhanced gradually when mild
inorganic bases such as Na2CO3, MgCO3, K2CO3, and Cs2CO3 were employed. Although
comparable yield of 8d was obtained in presence of K2CO3, and Cs2CO3, the former was chosen
for our reaction because of its easy availability and cost-effectivity. After careful tuning of the
reaction time, maximum yield (84%) of product 8d was obtained upon employing MBM as the
7

brominating agent and K2CO3 as base in DMF medium under stirring condition at room
temperature for 2h (Table 2, entry 15). With the optimized condition in hand, the scope and
generality of this reaction was next assessed by employing various starting compound 2 with a
variety of electron donating and electron withdrawing substituents in phenolic ring (Scheme 3,
Table 3).23 The results summarized in Table 3 show that it is a very general reaction with high
yields of products 8a-o. All the products were fully characterized by IR, 1H NMR, 13C NMR and
elemental analyses.
Table 2 Optimization of reaction conditions for the synthesis of 8d from 2d.a The bold values
indicates the maximum yield of the product at that particular reaction condition
Entry
Reagent (1.2 equiv.)
MBM
NBS
Base (1 equiv.)
Time (h)
Yield (%)b
45
1
2
3
4
–
–
–
–
12
12
12
12
c
–
–
c
Br2
1,3-dibromo-5,5-dimethyl
hydantoin
MBM
c
–
5
6
Et3N
pyrrolidine
piperidine
pyridine
NaOH
Na2CO3
MgCO3
K2CO3
12
12
12
12
12
12
12
12
12
6
51
54
56
58
MBM
MBM
MBM
MBM
MBM
MBM
MBM
MBM
7
8
d
9
–
10
11
12
13
14
15
16
59
61
84
83
84
84
65
Cs2CO3
K2CO3
MBM
MBM
MBM
K2CO3
K2CO3
2
1
a all the reactions are performed in DMF at room temperature
b isolated yields.
c mixture of products obtained.
d decomposition of MBM occurred.
8

O
CN
CN
O
NH
Br
(9)
R
O
O
N
H
K2CO3, DMF, RT
2 h, Stirring
O
OH
R
8a-o
2a-o
Scheme 3. Synthesis of 3H,3′H-spiro[benzofuran-2,1′-isoindole]-3,3′-dione 8 from adduct 2
O1
C8
C6
C7
N1
C5
C2
C4
C1
O2
C3
C9
O3
C10
C11
C15
C14
C12
C13
C16
Figure 2. ORTEP diagram of the X-ray crystal structure of compound 8d with the atomic
numbering scheme (CCDC No. 962750).
Table 3 Synthesis of 3H,3′H-spiro[benzofuran-2,1′-isoindole]-3,3′-diones 8 from adducts 2
Melting
Entry
Adduct (2)a
Product (8)
Yield Point
(%)b (oC)
9

O
1
O
NH
O
88
198-
200
O
N
H
O
OH
8a
2a
O
2
O
NH
O
86
220-
221
O
N
H
O
OH
8b
2b
O
3
O
NH
O
O
N
H
83
240-
242
O
OH
8c
2c
O
4
O
NH
O
84
190-
192
O
N
H
O
OH
8d
2d
O
5
O
NH
O
82
296-
297
O
N
H
O
Cl
OH
8e
Cl
2e
10

O
6
O
Cl
NH
O
84
190-
192
O
N
H
O
Cl
OH
8f
2f
O
7
O
F
NH
O
O
N
H
81
196-
198
O
F
OH
8g
2g
O
8
9
O
Br
NH
O
85
82
252-
254
O
N
H
O
Br
OH 2h
8h
O
O
Ph
NH
O
O
N
H
250-
252
O
Ph
OH
8i
2i
O
10
O
H3CO
NH
O
O
N
H
80
250-
251
O
8j
H3CO
OH
2j
O
11
O
H3CO2C
NH
O
O
N
H
83
240-
241
O
8k
H3CO2
C
OH 2k
11

O
12
O
Cl
NH
80
245-
246
O
O
N
H
O
Cl
OH
8l
2l
O
13
O
NH
O
75
234-
235
O
N
H
O
OH
8m
2m
O
14
15
O
NH
O
78
73
272-
274
O
N
H
O
OH 2n
8n
O
O
Cl
NH
O
290-
292
O
N
H
O
Cl
Cl
OH
8o
Cl
2o
a crude adducts 2 were used in all reactions.
b isolated yields w. r. t. adducts 1.
The formation of compound 8 may be explained on the basis of initial bromination of the
amide nitrogen of 2 by MBM in presence of base to form the intermediate 10 (Scheme 4).
Alternatively the enolic form 7 may undergo C-bromination with the help of MBM to form
intermediate 11. In presence of base both the intermediates 10 and 11 may eliminate HBr to form
intermediate 12. Finally the phenolic hydroxyl group may attack the carbon atom of C=N bond
of 12 intramolecularly to form the spiro compound 8. Since the reaction also takes place to some
12

2
extent without any base (Table 2, entry 1), the intermediate 11 may undergo intramolecular SN
type reaction to form the final cyclic compound 8 directly without formation of intermediate 12.
Therefore, C-brominated 11 is the most probable intermediate in the formation of spiro
isoindoles 8. It was not possible to isolate any of the intermediates under the reaction conditions.
O
O
NH
NH
CN
CN
CN
Br
OH
O
CN
9
Br
9
OH
OH
R
R
O
2
O
7
NH
N
Br
Br
O
O
O
OH
R
OH
R
3
N
11
10
2
H
O
O
R
12
O
NH
O
O
8
R
Scheme 4. Plausible mechanism for the formation of spiro compound 8
In conclusion, we have successfully developed an efficient two-step methodology for the
synthesis of potentially bioactive 3H,3′H-spiro[benzofuran-2,1′-isoindole]-3,3′-diones.
13

Utilization of non-toxic organo-brominating agent monobromomalononitrile in the synthesis of
spiro compounds is new and environmental friendly. The selective formation of only one product
in presence of monobromomalononitrile compared to other brominating agents such as NBS, Br2
and 1,3-dibromo-5,5-dimethyl hydantoin shows that monobromomalononitrile cannot brominate
even the activated phenolic rings. The present methodology will attract organic and
pharmaceutical chemists due to the utilization of simple and easily available starting materials
and non-hazardous brominating agent, good yields of the products, high atom-economy and
operational simplicity.
Acknowledgements
A. K. and K. D. thank the University Grant Commission (UGC) and S. P. thanks the Council of
Scientific and Industrial Research (CSIR), New Delhi, India respectively for offering them
research fellowship. 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/
References and notes
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17

(c) Pathak, S.; Kundu, A.; Pramanik, A. Tetrahedron Lett. 2011, 52, 5180; (d) Debnath, K.;
Pathak, S.; Pramanik, A. Tetrahedron Lett. 2014, 55, 1743; (e) Das, S.; Fröhlich, R.; Pramanik,
A. Synlett 2006, 207; (f) Das, S.; Fröhlich, R.; Pramanik, A. Org. Lett. 2006, 8, 4263; (g) Pathak,
S.; Debnath, K.; Pramanik, A. Beilstein J. Org. Chem. 2013, 9, 2344; (h) Pathak, S.; Pramanik,
A. Eur. J. Org. Chem. 2013, 4410; (i) Das, S.; Pramanik, A.; Fröhlich, R.; Patra, A. Tetrahedron
2004, 60, 10197.
22. (a) Poupelin, J.-P.; Saint-Ruf, G.; Perche, J.-C.; Roussey, J.-C.; Laude, B.; Narcisse, G.;
Bakri Logeais, F.; Hubert, F. Eur. J. Med. Chem. 1980, 15, 253; (b) Poupelin, J.- P.; Saint-Ruf,
G.; Perche, J.-C.; Lacroix, R.; Uchida-Ernouf, G.; Narcisse, G.; Hubert, F. Eur. J. Med. Chem.
1979, 14, 171; (c) Schmitt, G.; DinhAn, N.; Poupelin, J.-P.; Vebrel, J.; Laude, B. Synthesis 1984,
758; (d) Prabhakar, K. R.; Veerapur, V. P.; Bansal, P.; Vipan, K. P.; Reddy, K. M.; Barik, A.;
Reddy, B. K. D.; Reddanna, P.; Priyadarsini, K. I.; Unnikrishnana, M. K. Bioorg. Med. Chem.
2006, 14, 7113; (e) Malpani, Y.; Achary, R.; Kim, S. Y.; Jeong, H. C.; Kim, P.; Han, S. B.; Kim,
M.; Lee, C. -K.; Kim, J. N.; Jung, Y. –S. Eur. J. Med. Chem. 2013, 62, 534.
23. Typical procedure for the preparation of adduct 2d from 1d: A mixture of adduct 1d (1.0
mmol) and ammonium acetate (385 mg, 5.0 mmol) in acetic acid (5 mL) was refluxed for 1 h.
Then the cooled yellow reaction mixture was poured into ice-cold water and filtered to get
yellow solid mass 2d. The crude product 2d was used for further reaction without purification.
3-(2′-hydroxy-5′-methylbenzoyl)-2,3-dihydroisoindol-1-one (2d). Yellow solid, 220 mg (82%).
Mp 146-148°C, IR (KBr): 1644, 1717, 3193 cm-1. 1H NMR (300 MHz, CDCl3) δ: 11.39 (s, 1H),
7.82-7.79 (m, 1H), 7.74 (s, 1H), 7.44-7.41 (m, 3H), 7.35 (d, J = 8.4 Hz, 1H), 7.28-7.25 (m, 1H),
6.89 (d, J = 8.1 Hz, 1H), 6.19 (s, 1H), 2.34 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 197.8, 171.2,
18

161.9, 142.0, 140.7, 138.4, 131.9, 128.9, 128.8, 128.4, 124.2, 122.9, 118.5, 117.4, 60.2, 20.3.
Anal. calcd for C16H13NO3: C, 71.90; H, 4.90; N, 5.24 % found C, 71.72; H, 4.82; N, 5.14 %.
Typical procedure for the preparation of compound 8d from adduct 2d: The crude adduct
2d (obtained from 1.0 mmol of 1d) was dissolved in dimethylformamide (5 mL) at room
temperature. Then monobromomalononitrile (174 mg, 1.2 mmol w. r. t. 1d) and K2CO3 (1.0
mmol w. r. t. 1d) were added and the resulting mixture was stirred at room temperature for 2 h.
After the completion of the reaction (monitored by TLC), the reaction mixture was poured into
ice-cold water and extracted with ethylacetate and concentrated under reduced pressure. The
solid mass was purified by column chromatography (EtOAc/Hexane) to get pure product 8d.
5-Methyl-3H,3′H-spiro[benzofuran-2,1′-isoindole]-3,3′-dione (8d): Yellow solid, 215 mg (84%).
1
Mp 190-192°C, IR (KBr): 1628, 1725, 3223 cm-1. H NMR (300 MHz, DMSO-d6) δ: 9.41 (s,
1H), 7.81-7.77 (m, 2H), 7.71-7.58 (m, 3H), 7.32-7.26 (m, 2H), 2.35 (s, 3H). 13C NMR (75 MHz,
DMSO-d6) δ: 195.9, 169.7, 169.6, 141.8, 141.5, 133.8, 133.1, 131.5, 124.8, 123.9, 123.3, 122.3,
119.5, 113.8, 95.3, 20.3. Anal. calcd for C16H11NO3: C, 72.45; H, 4.18; N, 5.28 % found C,
72.24; H, 4.08; N, 5.17 %.
5-chloro-3H,3′H-spiro[benzofuran-2,1′-isoindole]-3,3′-dione (8f): Brown solid, 240 mg (84%).
1
Mp 190-192°C; IR (KBr): 1635, 1735, 3280 cm-1; H NMR (300 MHz, DMSO-d6) δ: 9.38 (s,
13
1H), 7.90-7.87 (m, 2H), 7.76 (d, J = 6.6 Hz, 1H), 7.65-7.57 (m, 2H), 7.43-7.37 (m, 2H); C
NMR (75 MHz, DMSO-d6) δ: 195.1, 169.8, 169.4, 141.3, 140.0, 133.9, 131.8, 131.7, 127.7,
124.8, 124.0, 122.7, 121.0, 116.1, 95.9; Anal. calcd for C15H8NO3Cl: C, 63.06; H, 2.82; N, 4.90
% found C, 62.88; H, 2.75; N, 4.81 %.
19

5-methoxy-3H,3′H-spiro[benzofuran-2,1′-isoindole]-3,3′-dione (8j): Yellow solid, 225 mg
1
(80%). Mp 250-251°C; IR (KBr): 1638, 1718, 3089 cm-1; H NMR (300 MHz, DMSO-d6) δ:
9.44 (s, 1H), 7.80 (d, J = 6.3 Hz, 1H), 7.68-7.60 (m, 2H), 7.51 (dd, J1 = 9.0 Hz, J2 = 2.7 Hz, 1H),
13
7.36-7.33 (m, 2H), 7.27 (d, J = 2.7 Hz, 1H), 3.83 (s, 3H); C NMR (75 MHz, DMSO-d6) δ:
195.7, 169.2, 166.1, 155.2, 141.5, 133.4, 131.6, 131.1, 129.1, 123.5, 121.9, 119.3, 114.8, 105.7,
95.3, 56.1; Anal. calcd for C16H11NO4: C, 68.32; H, 3.94; N, 4.98 % found C, 68.14; H, 3.87; N,
4.89 %.
24. Crystallographic data for the structure 2d and 8d in this Letter have been deposited with
Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 962748 and
CCDC 962750, respectively. Copies of the data can be obtained, free of charge via the website
www.ccdc.cam.ac.uk/data_request/cif.
Graphical Abstract
20

Facile synthesis of 3H, 3′H-spiro[benzofuran-2,1′-isoindole]-3,
3′-diones using monobromomalononitrile (MBM) as an efficient
organo-brominating agent
Ashis Kundu, Sudipta Pathak, Kamalesh Debnath and Animesh Pramanik*
O
O
O
NH
OH
BrCH(CN)2
NH4OAc
R
O
R
AcOH, Reflux
K2CO3, DMF, R.T.
2 h, stirring
O
N
H
HO
O
O
OH
R
15 examples
73-88%
15 examples
21