Facile synthesis of substituted pyrrole-fused isocoumarins from ninhydrin

Article abstract of DOI:10.1016/j.tetlet.2011.07.133

A simple and efficient procedure has been developed for the synthesis of substituted pyrrole-fused isocoumarins from easily available ninhydrin. The cyclic hemiaminal dihydroxy-indenopyrroles, the adducts of ninhydrin with enamines of acetylacetone, give pyrrole-fused isocoumarins upon heating in acidic medium. The process constitutes an interesting acid-catalyzed rearrangement to eight-membered lactams followed by intramolecular cyclization involving the amino and keto groups.

Full text of DOI:10.1016/j.tetlet.2011.07.133

Tetrahedron Letters 52 (2011) 5180–5183
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile synthesis of substituted pyrrole-fused isocoumarins from ninhydrin
⇑
Sudipta Pathak, Ashis Kundu, Animesh Pramanik
Department of Chemistry, University of Calcutta, 92, A.P.C. Road, Kolkata 700 009, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient procedure has been developed for the synthesis of substituted pyrrole-fused iso-
coumarins from easily available ninhydrin. The cyclic hemiaminal dihydroxy-indenopyrroles, the adducts
of ninhydrin with enamines of acetylacetone, give pyrrole-fused isocoumarins upon heating in acidic
medium. The process constitutes an interesting acid-catalyzed rearrangement to eight-membered lac-
tams followed by intramolecular cyclization involving the amino and keto groups.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 16 June 2011
Revised 26 July 2011
Accepted 28 July 2011
Available online 5 August 2011
Keywords:
Ninhydrin
Primary amine
Acid-catalyzed reaction
Pyrrole-fused isocoumarins
Isocoumarins are an important class of heterocyclic compounds
that exhibit diverse kinds of biological activities, such as antiallergic,
antimicrobial,1,2 immunomodulatory,3 cytotoxicity,4 antifungal,5
antiinflammatory,6 antiangiogenic,7 and antimalarial.8 These can
be isolated from various sources, such as plants, molds, bacteria,
and lichens.9 Bergenin, a naturally occurring isocoumarin, isolated
from medical plants shows mild anti-HIV activity10 as well as anti-
hepatotoxic11 and anti-ulcer activity.12 Angelis et al. reported the
synthesis of various isocoumarin derivatives which can act as estro-
gen beta selective ligands.13 The estrogen receptors (ERs), members
of the nuclear hormone receptor superfamily, mediate the activity of
estrogens in many different organs, including the reproductive, skel-
etal, cardiovascular, and central nervous system.14–16
There are numerous examples of natural products which con-
tain isocoumarin type of moiety.17 Isocoumarin molecules are also
utilized in the synthesis of several important heterocyclic com-
pounds, such as isoquinolines, isocarbostyrils, and isochromenes.
There are several reports of the synthesis of substituted isocouma-
rins.18 The most common method for the synthesis of isocoumarin
rings is by transition-metal catalyzed heteroannulation reac-
tions.19 Previously we developed a route to synthesize benzofuro-
isocoumarin from ninhydrin where one benzofuran ring is fused
with isocoumarin.20a Here we plan to synthesize another class of
isocoumarin compounds fused with pyrrole ring. Although there
are several methods for the synthesis of substituted isocouma-
rins,18 there has not been a single investigation for the construction
of the isocoumarin derivative fused with an N-aryl/alkyl substi-
tuted pyrrole ring. In continuation of our research interest in the
synthesis of various heterocyclic compounds with ninhydrin,20
we wish to report here a general and efficient method for the syn-
thesis of isocoumarin fused with an N-aryl/alkyl substituted
pyrrole.
Initially various primary amines were condensed with acetylace-
tone to prepare a series of adducts 1a–n (Scheme 1). Subsequently
these adducts were reacted with ninhydrin in acetic acid medium
to furnish C-2 alkylated 1,3-indanediones 2a–n in very good yields
(Table 1).21 The adducts so formed preferentially remain in the cyclic
hemiaminal dihydroxy-indenopyrroles 3a–n. This is the first ever
report of the formation of dihydroxy-indenopyrroles using acetyl-
acetone as 1,3-diketone and also with N-substitution.22 Similar type
of adducts of ninhydrin with phenols are found to show anti-inflam-
matory and analgesic activities.23 It should be mentioned that both
aromatic and aliphatic primary amines are used to obtain adducts
3a–n.
It is interesting to note that ethylenediamine also forms adduct
3n which is dimeric in nature (Fig. 1). From NMR studies it has
been confirmed that all adducts remain in the cyclic hemiaminal
form 3.24 Interestingly when these adducts 3 are heated on a water
bath for 5–20 min in acetic acid with a catalytic amount of conc.
H2SO4, pyrrole-fused isocoumarins 4a–n are formed in very good
yields (Scheme 1, Table 2).21 The formations of pyrrole-fused iso-
coumarins are very facile probably due to aromatic stabilization.
It should be noted that the adduct 3n remains in a conformation
without any symmetry. On the other hand the rearranged molecule
4n remains in a symmetric conformation (Fig. 1), confirmed by 1
H
and 13C NMR spectroscopy. The isolated pure compounds 4a–n are
yellowish white solids and are fully characterized by 1H and 13C
NMR spectroscopy.24 The X-ray crystal structures of 3a and 4a,
shown in Figure 2 further confirm the product formation.25 The
formation of dimeric product 4n is confirmed by high resolution
mass spectroscopy.
⇑
Corresponding author. Tel.: +91 33 2484 1647; fax: +91 33 2351 9755.
E-mail address: animesh_in2001@yahoo.co.in (A. Pramanik).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.133

S. Pathak et al. / Tetrahedron Letters 52 (2011) 5180–5183
5181
O
Ninhydrin
OH
Acetic acid
O
Acetylacetone + NH2R
HR
N
Room Temperature
Stirring
O
O
1a-n
N
2a-n
R
R
O
Acetic acid
O
O
N
OH
H2SO4(0.5 ml)
OH
O
HO
Heating at 85 oC
5-20 min
O
O
N
R
O
HN
O
R
4a-n
3a-n
Scheme 1. Synthesis of substituted pyrrole-fused isocoumarins 4a–n from ninhydrin.
Table 1
Formation of 3a–n from 1a–n
O
O
O
O
OH
O
HO
Entry R of NH2R
Adducts(3a– Time
Yield
(%)
Melting Point
(°C)
n)
(min)
N
N
1
2
H
3a
3b
15
90
87
210
186
15
N
N
3
4
3c
20
30
88
85
180
198
OH
OH
3d
O
O
Cl
O
O
5
6
3e
3f
35
40
80
75
185
188
O
3n
4n
Cl
Figure 1. Structures of compounds 3n and 4n.
7
8
3g
3h
30
30
90
89
105
195
Table 2
Formation of 4a–n from 3a–n
Cl
OMe
Entry Adducts
Products
Time
(min)
Yield
(%)
Melting Point
(°C)
MeO
(3)
(4)
9
3i
45
82
180
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
5
6
5
7
10
6
7
9
6
7
6
6
7
85
90
95
94
93
85
89
90
80
80
90
78
70
53
320
150
182
248
262
205
258
220
172
236
260
>320
>320
>320
OH
10
11
12
3j
30
30
40
73
86
87
192
93
Br
NO2
3k
3l
210
9
10
11
12
13
14
NO2
13
14
3m
3n
30
90
80
85
218
>320
20
The formation of isocoumarin derivatives 4 from adducts 3 can
be explained on the basis of the proposed mechanism depicted in
Scheme 2 which is in accordance to our previous results.20a,g In
acidic condition, protonation of the carbonyl group of the bicy-
clo[3.3.0]octano system 3 initiates the breaking of the central
C–C bond to afford an eight-membered lactam intermediate 5
which undergoes to tautomeric keto form 6. Subsequently the OH
group which is in alpha position to carbonyl group attacks the
amide carbonyl to break the amide bond in intermediate 6 resulting
in the formation of intermediate 7 with isocoumarin skeleton. Fi-
nally, the intramolecular nucleophic attack of amino group to the
carbonyl carbon followed by dehydration produces pyrrole-fused
isocoumarins 4a–n. It was not possible to isolate any of the inter-
mediates 5–7 under the reaction conditions (Scheme 2).
In conclusion, the substituted pyrrole-fused isocoumarins
appear to possess a number of biological properties but have been
proven difficult to access synthetically. We have developed a con-
venient and efficient methodology for synthesizing a diverse range
of N-substituted pyrrole-fused isocoumarins under mild reaction
conditions and without using any metals or expensive reagents.
The necessary starting materials and reagents are easily available.
To the best of our knowledge, this is the first time that the synthe-
sis of highly substituted pyrrole-fused isocoumarins has been
accomplished.

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S. Pathak et al. / Tetrahedron Letters 52 (2011) 5180–5183
Figure 2. ORTEP diagram of 3a and 4a with atom numbering scheme. Thermal ellipsoids are shown at the 50% probability.
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N
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O
O
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O
4
Scheme 2. Proposed mechanism for formation of 4 from 3.
21. (a) General procedure for the synthesis of compounds (3):
A mixture of
acetylacetone (1.1 mmol) and primary amine (1.0 mmol) was heated on a
water bath at 85 °C for 15 min. Then the reaction mixture was poured into a
solution of ninhydrin (0.25 g, 1.1 mmol) in acetic acid (10 ml). After stirring at
room temperature for 15–90 min (as mentioned in Table 1), the reaction
Acknowledgments
mixture was poured into cold water.
A yellow solid was filtered. Solid
S.P. and A.K. thank CSIR and UGC, New Delhi, India, respectively
for a Junior Research Fellowship (JRF). The authors are grateful to
the University of Calcutta for providing financial support.
compound was crystallized from acetone and hexane mixture.
(b) General procedure for the synthesis of compounds (4): Concentrated H2SO4
(0.5 ml) was added to a solution of dihydroxy-indenopyrroles 3 (0.2 g) in acetic
acid (10 ml). The reaction mixture was warmed on a water bath at 85 °C for 5–
20 min (as mentioned in Table 2). The initial yellowish color of the solution
was intensified to red. Then it was poured into ice cold water to obtain
yellowish white solid products. The compounds were purified by
crystallization technique using acetone and petroleum ether as mixed solvents.
22. (a) Hemmerling, H.-J.; Reiss, G. Synthesis 2009, 985; (b) Chatterjie, N.; Shapiro,
R.; Quo, S.-G.; Stephani, R. A. Tetrahedron Lett. 1975, 16, 2535; (c) Patent: W.O.
040547 A1, 2008.; (d) Yavari, I.; Seyfi, S.; Nematpour, M.; Hossaini, Z. Helv.
Chim. Acta 2010, 93.
Supplementary data
Supplementary data (IR, 1H, 13C data of compounds 3b–n and 4b–
n and crystallographic data for 3c) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2011.07.133.
23. 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.; Unnikrishnan, M. K. Bioorg.
Med. Chem. 2006, 14, 7113.
References and notes
24. 1-Acetyl-3a,8a-dihydroxy-2-methyl-3a,8a-dihydro-3H-3-aza-cyclopenta[a]inden-
8-one (3a): 1H NMR (300 MHz, D6-DMSO): d 9.01 (br s, NH), 7.70–7.83 (m, 2H),
7.63 (d, J = 13.2 Hz, 1H), 7.51 (t, J = 7.1 Hz, 1H), 6.52 (br s, 1H), 5.79 (br s, 1H),
2.21 (s, 3H), 2.03 (s, 3H).13C NMR (75 MHz, D6-DMSO): d 200.5, 193.1, 159.8,
150.3, 135.8, 134.5, 129.9, 124.8, 123.0, 105.6, 91.5, 85.6, 29.2, 15.5. IR(KBr):
3271, 1712 cmÀ1. Anal. Calcd for C14H13NO4: C, 64.86; H, 5.05; N, 5.40 Found C,
64.80; H, 5.01; N, 5.34. 1-Acetyl-3a,8a-dihydroxy-3-(2-methoxyphenyl)-2-
methyl-3a,8a- dihydro-3-aza-cyclopenta[a]inden-8-one(3i): 1H NMR (300 MHz,
D6-DMSO): d 7.70–7.72 (m, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.40–7.49 (m, 3H),
7.05–7.15 (m, 2H), 6.98 (d, J = 8.2 Hz, 1H), 6.47 (d, J = 6.9 Hz, 1H), 6.19 (s, 1H),
3.37 (s, 3H), 2.42 (s, 3H), 1.87 (s, 3H). 13C NMR (75 MHz, D6-DMSO): d 200.5,
194.0, 160.8, 156.48, 134.81, 134.72, 131.5, 130.3, 129.8, 124.5, 124.2, 123.33,
1. Matsuda, H.; Shimoda, H.; Yoshikawa, M. Bioorg. Med. Chem. 1999, 7, 1445.
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S. Pathak et al. / Tetrahedron Letters 52 (2011) 5180–5183
5183
120.70, 112.0, 106.3, 94.6, 84.6, 55.1, 29.9, 14.4. IR(KBr): 3370, 1719 cmÀ1
.
140.0, 134.6, 131.7, 131.6, 130.7, 129.8, 125.4, 125.3, 121.4, 118.0, 117.6, 112.5,
112.2, 110.4, 55.8, 31.2, 12.0. IR(KBr): 1719 cmÀ1. HRMS (m/z in methanol):
calcd [M+Na] requires 370.1056, found 369.8876, [M+K] requires 386.0795,
found 385.8535. Anal. Calcd for C21H17NO4: C, 72.61; H, 4.93; N, 4.03 Found C,
72.55; H, 4.87; N, 3.97.
Anal. Calcd for C21H19NO5: C, 69.03; H, 5.24; N, 3.83 Found C, 68.98; H, 5.20; N,
3.80. 3-Acetyl-2-methyl-1H-4-oxa-1-aza-cyclopenta[a]naphthalen-5-one(4a):1H
NMR (300 MHz, CDCl3): d 12.3 (br s, 1H), 8.12 (d, J = 8.1 Hz, 1H), 7.79–7.83
(m, 2H), 7.41 (d, J = 7.8 Hz, 1H), 2.51 (s, 3H), 2.45 (s, 3H). 13C NMR (75 MHz,
CDCl3): d 191.6, 161.4, 137.1, 135.5, 130.7, 130.3, 125.8, 119.1, 117.7, 116.3,
110.1, 109.6, 30.3, 14.1. IR(KBr): 3332, 1707 cmÀ1. Anal. Calcd for C14H11NO3:
C, 69.70; H, 4.60; N, 5.81 Found C, 69.62; H, 4.57; N, 5.76. 3-Acetyl-1-(2-
methoxyphenyl)-2-methyl-4-oxa-1-aza-cyclopenta[a]naphthalen-5-one(4i): 1H
NMR (300 MHz, CDCl3): d 8.33 (d, J = 7.6 Hz, 1H), 7.62 (t, J = 7.5 Hz, 1H),
7.23–7.37 (m, 3H), 7.15–7.20 (m, 2H), 6.46 (d, J = 8.0 Hz, 1H), 3.75 (s, 3H), 2.74
(s, 3H), 2.36 (s, 3H). 13C NMR (75 MHz, CDCl3): d 193.6, 162.7, 155.8, 140.9,
25. Crystallographic data for the structure 3a, 3c, 4a in this Letter have been
deposited with Cambridge Crystallographic Data Center as supplementary
publication No. CCDC 827674, 827675, 827676, respectively. Copies of the data
can be obtained, free of charge on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK, (fax: +44 01223 336033 or e-mail:
deposit@ccdc.cam.ac.uk).