Synthesis of hexacyclic fused isocoumarin framework through selective domino multicyclizations under catalyst and solvent free conditions

Article abstract of DOI:10.1016/j.cclet.2014.03.022

A novel fused isocoumarin skeleton has been synthesized through selective domino multicyclizations by mixing homothallic acid and 2,3-diphenylacryloyl chloride at 200 °C under catalyst and solvent free reaction conditions. Six fused rings with two stereogenic centers were assembled in a convenient one-pot operation in good yield. The resulting hexacyclic fused isocoumarin skeleton and its stereochemistry was fully characterized and unambiguously confirmed by X-ray diffraction analysis.

Full text of DOI:10.1016/j.cclet.2014.03.022

G Model
CCLET 2906 1–5
Chinese Chemical Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
1
2
Original article
3
4
5
Synthesis of hexacyclic fused isocoumarin framework through
selective domino multicyclizations under catalyst and solvent free
conditions
a
a,
a
6
7
Q1 Tariq Mahmood Babar , Muhammad Moazzam Naseer *, Muhammad Khawar Rauf ,
b
c
a,
Humayun Pervez , Masahiro Abihara , Nasim Hasan Rama *
a
8
9
1
Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan
b
Institute of Chemical Sciences, Organic Chemistry Division, Bahauddin Zakariya University, Multan 60800, Pakistan
c
0
Department of Chemistry, Faculty of Engineering, Gifu University, Yanagido, Gifu 501-1193, Japan
A R T I C L E I N F O
A B S T R A C T
Article history:
A novel fused isocoumarin skeleton has been synthesized through selective domino multicyclizations by
mixing homothallic acid and 2,3-diphenylacryloyl chloride at 200 8C under catalyst and solvent free
reaction conditions. Six fused rings with two stereogenic centers were assembled in a convenient one-
pot operation in good yield. The resulting hexacyclic fused isocoumarin skeleton and its stereochemistry
was fully characterized and unambiguously confirmed by X-ray diffraction analysis.
ß 2014 Muhammad Moazzam Naseer and Nasim Hasan Rama. Published by Elsevier B.V. on behalf of
Chinese Chemical Society. All rights reserved.
Received 15 January 2014
Received in revised form 19 February 2014
Accepted 25 February 2014
Available online xxx
Keywords:
Hexacyclic
Fused isocoumarin
One pot
Catalyst and solvent free
1
1
1
2
1. Introduction
However,itismuchmoredesirable,ifonecouldformseveralbondsin 30
one go withoutisolating the intermediates and changing thereaction 31
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14
15
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19
20
21
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29
The assembly of complex polycyclic skeletons of chemical and
biomedical interest has become an important, challenging and
active area of research in modern organic chemistry [1]. Among
these skeletons, isocoumarin based fused ring system present in
many natural products (Fig. 1) shows a broad range of biological
activities [2]. In recent years, a variety of methods have been
developed to prepare these structurally complex fused skeletons
[3]. However, synthetic chemists are continuously searching for
the development of new, cleaner and efficient chemical transfor-
mation methodologies, or modifications in the established
synthetic pathways to ensure eco-friendly and cost effective
synthesis with minimal or no use of toxic chemicals.
Till date, excellent region-, chemo-, diastereo- and enantio-
selectivitiesareobtainedforthepreparationofcomplexmoleculesby
developing several highly selective procedures [4]. The procedure
usuallyusedfortheconstructionofsuchorganiccompoundsinvolves
a step-wise formation of individual bonds in the target molecule.
conditions. The waste produced in such synthetic procedures is very 32
small as compared to step-wise pathways. Therefore, from the 33
synthetic point of view, one-pot synthesis of fused-ring systems is an 34
attractive procedure for searching bioactive compounds.
35
Coumarinderivatives [5] areimportant synthetictargetsbecause 36
of possessing diverse biological applications [6]. They are also 37
known to have vasodilatory [7], anticoagulant [8], anti-HIV [9], 38
antitumor [10] and anti-inflammatory [11] properties. The fluores- 39
cent properties of some isocoumarin derivatives are also reported 40
[12]. Herein, we reportone-potsynthesis ofnovel fused isocoumarin 41
framework through highly selective domino multicyclizations 42
under catalyst and solvent free reaction conditions. The resulting 43
fused isocoumarin framework is an interesting scaffold for drug 44
design and discovery and can play an important role in pharmaceu- 45
tical research.
46
47
48
2. Experimental
2.1. Materials and methods
*
Corresponding authors.
All reagents and solvents were used as obtained from the 49
supplier or recrystallized/redistilled as required. Thin layer 50
E-mail addresses: moazzam@qau.edu.pk (M.M. Naseer), nhrama@qau.edu.pk
(
N.H. Rama).
http://dx.doi.org/10.1016/j.cclet.2014.03.022
1
001-8417/ß 2014 Muhammad Moazzam Naseer and Nasim Hasan Rama. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Please cite this article in press as: T.M. Babar, et al., Synthesis of hexacyclic fused isocoumarin framework through selective domino
multicyclizations under catalyst and solvent free conditions, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.03.022

G Model
CCLET 2906 1–5
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T.M. Babar et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
by the disappearance of gas evolution. Excess thionyl chloride was
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
removed under reduced pressure to afford 2,3-diphenylacryloyl
chloride. Homophthalic acid (0.54 g, 3 mmol) was then added to it
and the mixture was heated first for 3.5 h at 200 8C and then cooled
to room temperature. Addition of aqueous solution of sodium
carbonate (5%, 200 mL), followed by filtration and washing
thoroughly with water furnished the crude product, which was
recrystallized in toluene to give compound 6 in pure form (68%).
ꢀ
1
Mp: 135–136 8C; IR (KBr, cm ):
n
):
2918 (C–H), 1704 (C 55 O), 1569
8.11 (dd, 1H, J = 1.2, 7.5 Hz),
1
(
C 55 C); H NMR (300 MHz, CDCl
3
d
7
.91 (d, 1H, J = 7.5 Hz), 7.88–7.82 (m, 1H), 7.59–7.19 (m, 12H), 6.98
1
3
(
dd, 2H, J = 1.2, 7.5 Hz), 4.96 (s, 1H); C NMR (75 MHz, CDCl
3
):
d
2
1
1
04.6, 161.4, 151.1, 142.7, 137.5, 135.8, 135.7, 135.3, 133.1, 130.6,
28.8, 128.7, 128.6, 128.4, 128.2, 127.4, 124.9, 124.4, 123.6, 122.7,
+
07.8, 62.7, 48.2, 31.0; MS [MALDI-TOF] (m/z) 427.13 [M+H ]
(
18 3
100), 428.13 (33), 429.13 (5). Anal. Calcd. for C30H O : C, 84.49;
H, 4.25; Found: C, 84.53; H, 4.23.
3. Results and discussion
84
We commenced our studies by reacting equimolar quantities of
85
homophthalic acid 1 and 2,3-diphenylacryloyl chloride 2 at 200 8C
with an aim of getting isocoumarin derivative, 3-(1,2-diphenylvi-
nyl)-1H-isochromen-1-one 3 [13] (Scheme 1 and Fig. S1 in
Supporting information). However, instead of obtaining the
expected product 3, compound 4, i.e. 3-phenyl-1H-isochromen-
1-one [14] and the novel fused hexacyclic isocoumarin framework
6, formed by the domino multicylization reaction, were isolated in
75% and 1% yields, respectively (Table 1, entry 1). Structure of the
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
Fig. 1. Some representative natural products.
5
5
5
5
5
5
5
5
5
6
6
6
1
2
3
4
5
6
7
8
9
0
1
2
chromatography (TLC) was performed using aluminum sheets
(Merck) coated with silica gel 60 F254. The melting points of
compounds were determined using capillary tubes and an
electrothermal melting point apparatus, model MP-D Mitamura
Riken Kogyo, Japan. IR spectra of compounds were recorded on a
Bio-Rad FTS 3000 MX spectrophotometer (400–4000 cm ). NMR
spectra were recorded using a Bruker AM-300 spectrometer and
chemical shifts are reported in ppm versus tetramethylsilane with
either tetramethylsilane or the residual solvent resonance used as
an internal standard. Mass spectra were acquired on a Bruker
Omniflex MALDI-TOF instrument and elemental analyses were
carried out with a LECO-183 CHNS model.
ꢀ1
1
novel fused ring system 6 was established through spectral (IR, H
1
3
NMR, C NMR, COSY, NOESY, MS) and single crystal X-ray analyses
(Fig. 2, Table 2). This unprecedented observation prompted us to
pursue further the domino cyclization reaction from both the
mechanistic as well as synthetic viewpoints. Accordingly, we
retroanalyzed the fused isocoumarin skeleton 6 (Fig. S2 in
Supporting information); it was hypothesized that some of the
2,3-diphenylacryloyl chloride 2 might be cyclized under the
6
3
2.2. Procedure for the synthesis of hexacyclic fused isocoumarin (6)
conditions to give 2-phenyl-1H-inden-1-one 5 [15], which reacted
with the already observed 3-phenyl-1H-isochromen-1-one 4
through Michael addition reaction (Fig. 3). To check our hypothe-
sis, the concentration of 2 was gradually increased under the same
reaction conditions. To our delight, the yield of 6 significantly
64
65
66
A mixture of 2,3-diphenylacrylic acid (2.07 g, 9 mmol) and
thionyl chloride (1 mL) was heated in the presence of a few drops
of DMF for 30 min at 70 8C. Completion of reaction was indicated
Scheme 1. Novel domino multicyclization reaction with all possible byproducts.
Table 1
Optimization of reaction conditions for the synthesis of 6.
a
a
a
Entry
Reactants ratio (1:2)
Temp. (8C)
Time (h)
3 (%)
4 (%)
5 (%)
6 (%)
1
2
3
4
5
6
1:1
1:2
1:3
1:3
1:3
1:3
200
200
200
200
200
200
2
0
0
0
0
0
0
75
45
28
7
0
0
0
0
3
1
20
30
46
67
68
2
2
3
4
0
3.5
0
Trace
a
Isolated yield.
Please cite this article in press as: T.M. Babar, et al., Synthesis of hexacyclic fused isocoumarin framework through selective domino
multicyclizations under catalyst and solvent free conditions, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.03.022

G Model
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T.M. Babar et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
3
Table 2
X-ray crystallographic data of 6.
Crystal data
Chemical formula
30 18 3
C H O
M
r
426.44
Crystal system, space group
1
Monoclinic, P2 /c
Temperature (K)
123
a, b, c ( A˚ )
10.726 (5), 15.309 (7),
3.867 (7)
1
b
V (A˚
(8)
113.005 (5)
2095.8 (17)
4
3
)
Z
Radiation type
Mo K
0.09
a
ꢀ
1
m
(mm
)
Crystal size (mm)
0.50 ꢁ 0.42 ꢁ 0.35
Data collection
Diffractometer
Rigaku/MSC Mercury
CCD diffractometer
–
Absorption correction
No. of measured, independent
16,708, 4757, 4470
and observed [I > 2s(I)]
reflections
R
int
0.031
0.649
(sin
u/l
)
max (A˚
ꢀ
1
)
Refinement
2
2
2
R[F > 2
s(F )], wR(F ), S
0.060, 0.121, 1.23
4757
No. of reflections
No. of parameters
No. of restraints
H-atom treatment
298
0
Fig. 2. ORTEP diagram of 6.
H-atom parameters
constrained
0.43, ꢀ0.18
D
i
max
,
D
i
min (e A˚
ꢀ
3
)
107
108
109
110
111
112
113
increased (1% ! 20%), while that of isocoumarin derivative 4
diminished (75% ! 45%) (Table 1, entry 2). Interestingly, when the
concentration of 2 was enhanced to 3 equivalents, the yield of 6
further increased (20% ! 30%), while that of
4
decreased
to cyclize. Thus, the reaction time was increased from 2 to 3 h. It 114
was found that the yield of 4 pronouncedly decreased (28% ! 7%), 115
while that of 6 increased (30% ! 46%) (Table 1, entry 4). 116
Surprisingly, further increase in the time duration (3 ! 4 h) led 117
(45% ! 28%) (Table 1, entry 3). At this stage, it was assumed that
the formation of 2-phenyl-1H-inden-1-one 5 compared with 3-
phenyl-1H-isochromen-1-one 4 was slow and it needed more time
O
OH
H
O
O
O
O
O
Ph
C
Ph
Cl
O
SOCl2
DMF
C
COOH
Ph
Ph
Ph
1
2
(
i) Ph
C
O
Ph
O
O
Ph
o
Ph
00 C
COOH
C
O
H
2
A
O
B
Ph
-CO2
-
H
Ph
O
o
Ph
2
00 C
(ii)
Ph
-
H O
2
C
O
O
Cl
O
O
5
O
O
4
C
O
O
O
O
Ph
air oxidation
Ph
5
Ph
Ph
Michael
Michael
(iii)
Ph
H
H
O
O
O
O
O
O
O
4
O
6
D
E
Fig. 3. Proposed mechanism for the synthesis of 6.
Please cite this article in press as: T.M. Babar, et al., Synthesis of hexacyclic fused isocoumarin framework through selective domino
multicyclizations under catalyst and solvent free conditions, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.03.022

G Model
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T.M. Babar et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
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b) W. Fan, Q. Ye, H.W. Xu, et al., Novel double [3+2+1] heteroannulation for
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184
185
186
187
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190
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250
251
252
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254
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256
257
258
259
260
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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42
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to the formation of compounds 5 and 6 in 3% and 67% yields,
respectively (Table 1, entry 5). It is pertinent to mention that
compound 4 was not isolated under the conditions, indicating that
compound 5 reacts with it very quickly as soon as it forms.
Interestingly, a slight decrease in the time duration (4! 3.5 h)
provided maximum yield (68%) of the fused compound 6 along with
a trace amount of compound 5 as an impurity (Table 1, entry 6).
The attractive feature of this domino reaction is demonstrated
by the fact that four new chemical bonds and three new rings were
readily formed in domino fashion. In addition, work-up of the
reaction is very simple. Water and phenylacetylene are the only
byproducts, which may be evaporated under the reaction
conditions/during the concentration of the reaction mixture,
making the work-up very convenient simply by adding water/
filtration/washing/recrystallization. Finally, it is important to
address here that only a single diastereomer of 6 was detected
first by spectroscopic and then by X-ray diffraction analysis (Fig. 2
and Table 2).
forming unprecedented dipyrazolo-fused 2,6-naphthyridines, Org. Lett. 15 (2013)
2
(c) B. Jiang, X. Wang, H.W. Xu, et al., Highly selective domino multicyclizations for
forming polycyclic fused acridines and azaheterocyclic skeletons, Org. Lett. 15
258–2261;
(
(
2013) 1540–1543;
d) M. Piltan, I. Yavari, L. Moradi, Tandem synthesis of functionalized hexaalkyl
benzoisoquinolinopyrrolonaphthyridine-hexacarboxylate, via isoquinoline based
multi-component reaction, Chin. Chem. Lett. 24 (2013) 979–983;
(
e) A.D. Melhado, W.E. Brenzovich, A.D. Lackner, F.D. Toste, Gold-catalyzed three-
component coupling: oxidative oxyarylation of alkenes, J. Am. Chem. Soc. 132
2010) 8885–8887;
(f) R.A. Yoder, J.N. Johnston,
polyolefin carbocyclizations to terpenes and steroids, Chem. Rev. 105 (2005)
730–4756.
(
A
case study in biomimetic total synthesis:
4
[
2] (a) P.C. Chao, C.C. Hsu, M.C. Yin, Anti-inflammatory and anti-coagulatory activi-
ties of caffeic acid and ellagic acid in cardiac tissue of diabetic mice, Nutr. Metab. 6
(
(
2009) 33;
b) G. Cozza, A. Gianoncelli, P. Bonvini, et al., Urolithin as a converging scaffold
linking ellagic acid and coumarin analogues: design of potent protein kinase CK2
inhibitors, ChemMedChem 6 (2011) 2273–2286;
(
c) H.A. De Abreu, I.A.D.S. Lago, G.P. Souza, et al., Antioxidant activity of (+)-
bergenin – a phytoconstituent isolated from the bark of Sacoglottis uchi Huber
Humireaceae), Org. Biomol. Chem. 6 (2008) 2713–2718;
(
The mechanism for this domino multicyclization reaction is
proposed and shown in Fig. 3. It can be divided into three steps. The
first step involves ring closure cascade reaction, which consists of
regioselective condensation of acyl chloride 2 with homophthalic
acid 1 leading to A and HCl (2 to A), intramolecular cyclization (A to
(d) J.H. Weisburg, A.G. Schuck, S.E. Reiss, et al., Ellagic acid, a dietary polyphenol,
selectively cytotoxic to HSC-2 oral carcinoma cells, Anticancer Res. 33 (2013)
1
829–1836;
(e) T.Y. Kao, Y.C. Chung, Y.C. Hou, et al., Effects of ellagic acid on chemosensitivity
to 5-fluorouracil in colorectal carcinoma cells, Anticancer Res. 32 (2012) 4413–
4418;
(
f) Y.S. Kim, T. Zerin, H.Y. Song, Antioxidant action of ellagic acid ameliorates
paraquat-induced A549 cytotoxicity, Biol. Pharm. Bull. 36 (2013) 609–615.
3] (a) F. Nemati, R. Saeedirad, Nano-Fe encapsulated-silica particles bearing
2
B), removal of CO , phenyl acetylene and phenyl migration in a
concerted fashion (B to C), and finally dehydration (C to 4). The
second step includes intramolecular cyclization of 2 to give
intermediate 5. In the third step, double Michael addition reaction
between 4 and 5 leads to intermediate E through D, which after
aerobic oxidation, provides thermodynamically stable hexacyclic
fused isocoumatin framework 6. This mechanism has been
partially supported by an experiment in which the isolated
intermediates 4 and 5 were reacted at 200 8C under solvent and
catalyst free conditions; the hexacyclic product 6 was again
generated in 66% yield (Scheme S1 in Supporting information). To
the best of our knowledge, the synthetic strategy and mechanistic
sequences described herein have not been reported so far.
[
3 4
O
sulfonic acid groups as a magnetically separable catalyst for green and efficient
synthesis of functionalized pyrimido[4,5-b]quinolines and indeno fused pyr-
ido[2,3-d]pyrimidines in water, Chin. Chem. Lett. 24 (2013) 370–372;
(
b) W.C. Gong, Y. Liu, J. Zhang, et al., Regio- and stereoselective [4+3] cycloaddi-
tion towards fused 5,7,6-tricyclic skeletons, Chem. Asian J. 8 (2013) 546–551;
c) S. Yasuike, M. Niwa, K. Yamaguchi, T. Tsuchiya, J. Kurita, Synthesis of 1-
(
stibaphenalenes, the first example of group 15 phenalenes, via a 1,5-dilithium
intermediate, Chem. Lett. 30 (2001) 554–555;
(d) J.J. Kaloko, Y.H. Gary, T.I. Ojima, One-step formation of fused tetracyclic
skeletons from cyclohexene-diynes and carbon monoxide through Rh(I)-cata-
lyzed [2+2+2+1] cycloaddition reaction, Chem. Commun. (2009) 4569–4571;
(e) H. Mizoguchi, H. Oguri, K. Tsuge, H. Oikawa, Divergent and expeditious access
to fused skeletons inspired by indole alkaloids and transtaganolides, Org. Lett. 11
(
(
2009) 3016–3019;
f) N. Saito, T. Ichimaru, Y. Sato, Ruthenium-catalyzed intramolecular [2+2+2]
cyclization of allene-yne-enes: construction of fused-tricyclic skeletons, Chem.
Asian J. 7 (2012) 1521–1523;
1
54
4. Conclusion
(g) S. Rostamizadeh, M. Nojavan, R. Aryan, H. Sadeghian, M. Davoodnejad, A novel
and efficient synthesis of pyrazolo[3,4-d]pyrimidine derivatives and the study of
their anti-bacterial activity, Chin. Chem. Lett. 24 (2013) 629–632;
(h) F. Shi, X.N. Zeng, X.D. Cao, et al., Design and diversity-oriented synthesis of
novel 1,4-thiazepan-3-ones fused with bioactive heterocyclic skeletons and
evaluation of their antioxidant and cytotoxic activities, Bioorg. Med. Chem. Lett.
155
156
157
158
159
160
161
162
163
164
Conclusively, a novel three component domino reaction was
used for the construction of unprecedented hexacyclic fused
isocoumarin framework. It is noteworthy for its cheap and readily
available starting materials, eco-friendly procedure, easy work-up
and potential biological applications of the resulting product. Our
future efforts will be focused on using various computational and
experimental methods for exploring the biological applications of
this novel fused ring system. The facile one pot synthetic procedure
may also be used to construct more useful and potential bioactive
derivatives of this fused isocoumarin skeleton.
2
2 (2012) 743–746.
[
4] (a) A. Ahmed, S. Dhara, J.K. Ray, Palladium-catalyzed and (KOBu)-Bu-t-promoted
C-aryl-O-alcoholic coupling: an efficient one-pot synthesis of oxygen containing
fused rings, Tetrahedron Lett. 54 (2013) 1673–1676;
(b) P. Sang, M. Yu, H.F. Tu, J.W. Zou, Y.H. Zhang, Highly regioselective synthesis of
fused seven-membered rings through copper-catalyzed cross-coupling, Chem.
Commun. 49 (2013) 701–703;
(c) A. Caruso, M.A. Siegler, J.D. Tovar, Synthesis of functionalizable boron-con-
taining pi-electron materials that incorporate formally aromatic fused borepin
rings, Angew. Chem. Int. Ed. 49 (2010) 4213–4217;
(d) M.A. Esteruelas, I. Fernandez, A. Herrera, et al., Multiple C–H bond activation
of phenyl-substituted pyrimidines and triazines promoted by an osmium poly-
hydride: formation of osmapolycycles with three, five, and eight fused rings,
Organometallics 29 (2010) 976–986;
1
65
Acknowledgment
1
1
66
67
We are highly grateful to the Higher Education Commission
(HEC), Govt. of Pakistan for financial support.
(e) D.R. Levine, A. Caruso, M.A. Siegler, J.D. Tovar, Meta-B-entacenes: new poly-
cyclic aromatics incorporating two fused borepin rings, Chem. Commun. 48
(
(
2012) 6256–6258;
f) S. Maiti, M.G.B. Drew, R. Mukhopadhyay, B. Achari, A.K. Banerjee, Convenient
1
68
Appendix A. Supplementary data
formation of six- to nine-membered carbocyclic rings by 2-pyridyl radical cycli-
zation: a generalized synthesis of pyridine-fused linear tricyclic systems, Synthe-
sis-Stuttgart (2005) 3067–3078;
1
1
69
70
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.cclet.2014.03.022.
0 0
(g) K. Niimi, S. Shinamura, I. Osaka, E. Miyazaki, K. Takimiya, Dianthra[2,3-b:2 3 -
f]thieno[3,2-b]thiophene (DATT): synthesis, characterization, and FET character-
istics of new p-extended heteroarene with eight fused aromatic rings, J. Am.
Chem. Soc. 133 (2011) 8732–8739;
1
71
References
(h) V. Novakova, J. Roh, P. Gela, J. Kunes, P. Zimcik, Azaphthalocyanines with fused
triazolo rings: formation of sterically stressed constitutional isomers, Chem.
Commun. 48 (2012) 4326–4328;
(i) L.A. Paquette, R.V.C. Carr, E. Arnold, J. Clardy, Electronic control of stereo-
selectivity. 5. Stereochemistry of singlet oxygen capture by cyclopentadiene rings
172
173
174
[1] (a) G.L. Adams, P.J. Carroll, A.B. Smith, Access to the Akuammiline family
of alkaloids: total synthesis of (+)-scholarisine A, J. Am. Chem. Soc. 135 (2013)
519–528;
Please cite this article in press as: T.M. Babar, et al., Synthesis of hexacyclic fused isocoumarin framework through selective domino
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2
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2
2
2
2
2
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2
2
2
2
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62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
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80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
fused to norbornyl and norbornenyl frameworks, J. Org. Chem. 45 (1980) 4907–
4913.
[5] (a) D. Du, Z.W. Wang, N-Heterocyclic carbene-catalyzed domino reactions of
formylcyclopropane 1,1-diesters: a new synthesis of coumarins, Eur. J. Org. Chem.
(2008) 4949–4954;
[10] (a) E. Budzisz, E. Brzezinska, U. Krajewska, M. Rozalski, Cytotoxic effects, alkylat- 297
ing properties and molecular modelling of coumarin derivatives and their phos- 298
phonic analogues, Eur. J. Med. Chem. 38 (2003) 597–603;
299
(b) D. Cooke, R. O’Kennedy, Comparison of the tetrazolium salt assay for succi- 300
nate dehydrogenase with the cytosensor microphysiometer in the assessment of 301
(b) M.A. Kinder, P. Margaretha, Photochemistry of 4H,7H-benzo[1,2-c: 4,3-
compound toxicities, Anal. Biochem. 274 (1999) 188–194;
302
0
c ]dipyran-4,7-dione, a twofold isocoumarin, Org. Lett. 2 (2000) 4253–4255;
(c) D. Egan, P. James, D. Cooke, R. OKennedy, Studies on the cytostatic and 303
cytotoxic effects and mode of action of 8-nitro-7-hydroxycoumarin, Cancer Lett. 304
(c) V. Nair, C.R. Sinu, R. Rejithamol, K.C.S. Lakshmi, E. Suresh, A novel NHC-
catalyzed transformation of 2H-chromene-3-carboxaldehydes to 3-methyl-2H-
chromen-2-ones, Org. Biomol. Chem. 9 (2011) 5511–5514;
(d) S. Ozcan, M. Balci, The chemistry of homophthalic acid: a new synthetic
strategy for construction of substituted isocoumarin and indole skeletons, Tetra-
hedron 64 (2008) 5531–5540;
(e) E.M. Phillips, M. Wadamoto, H.S. Roth, A.W. Ott, K.A. Scheidt, NHC-catalyzed
reactions of aryloxyacetaldehydes: a domino elimination/conjugate addition/
acylation process for the synthesis of substituted coumarins, Org. Lett. 11
(2009) 105–108;
(f) S.P. Waters, M.C. Kozlowski, Synthesis of the isocoumarin portion of the
rubromycins, Tetrahedron Lett. 42 (2001) 3567–3570.
118 (1997) 201–211;
(d) P. Hilgard, R.D. Thornes, Perspectives in cancer research anticoagulants in 306
treatment of cancer, Eur. J. Cancer 12 (1976) 755–762;
305
307
(e) U.S. Weber, B. Steffen, C.P. Siegers, Antitumor-activities of coumarin, 7- 308
hydroxy-coumarin and its glucuronide in several human tumor cell lines, Res. 309
Commun. Mol. Path. 99 (1998) 193–206.
310
[11] C.A. Kontogiorgis, K. Savvoglou, D.J. Hadjipavlou-Litina, Antiinflammatory and 311
antioxidant evaluation of novel coumarin derivatives, J. Enzym. Inhib. Med. Chem. 312
21 (2006) 21–29.
313
2+
[12] (a) H.S. Jung, P.S. Kwon, J.W. Lee, et al., Coumarin-derived Cu -selective fluo- 314
rescence sensor: synthesis, mechanisms, and applications in living cells, J. Am. 315
[6] (a) F. Borges, F. Roleira, N. Milhazes, L. Santana, E. Uriarte, Simple coumarins and
analogues in medicinal chemistry: occurrence, synthesis and biological activity,
Curr. Med. Chem. 12 (2005) 887–916;
Chem. Soc. 131 (2009) 2008–2012;
316
(b) X.G. Liu, J.M. Cole, P.G. Waddell, et al., Molecular origins of optoelectronic 317
properties in coumarin dyes: toward designer solar cell and laser applications, J. 318
(b) R. O’Kennedy, R.D. Thornes, Coumarins: Biology, Applications, and Mode of
Action, Wiley, Chichester, NY, 1997;
(c) M.E. Riveiro, N. de Kimpe, A. Moglioni, et al., Coumarins: old compounds
with novel promising therapeutic perspectives, Curr. Med. Chem. 17 (2010)
1325–1338.
Phys. Chem. A 116 (2012) 727–737.
[13] H. Kaji, M. Yamada, K. Nozawa, K. Kawai, S. Nakajima, Synthesis of antifungal 320
isocoumarins, Org. Prep. Proced. Int. 18 (1986) 253–262.
319
321
[14] (a) S.J. Cai, F. Wang, C.J. Xi, Assembly of 3-substituted isocoumarins via a Cul- 322
catalyzed domino coupling/addition/deacylation process, J. Org. Chem. 77 (2012) 323
[7] S. Vilar, E. Quezada, L. Santana, et al., Design, synthesis, and vasorelaxant and
platelet antiaggregatory activities of coumarin-resveratrol hybrids, Bioorg. Med.
Chem. Lett. 16 (2006) 257–261.
[8] O. Thastrup, J.B. Knudsen, J. Lemmich, K. Winther, Inhibition of human-platelet
aggregation by dihydropyrano and dihydrofuranocoumarins, a new class of
camp-phosphodiesterase inhibitors, Biochem. Pharmacol. 34 (1985) 2137–2140.
[9] D.L. Yu, M. Suzuki, L. Xie, S.L. Morris-Natschke, K.H. Lee, Recent progress in the
development of coumarin derivatives as potent anti-HIV agents, Med. Res. Rev. 23
(2003) 322–345.
2331–2336;
(b) T.L. Yao, R.C. Larock, Synthesis of isocoumarins and alpha-pyrones via elec- 325
trophilic cyclization, J. Org. Chem. 68 (2003) 5936–5942.
324
326
[15] (a) K. Katsumoto, C. Kitamura, T. Kawase, An indenone synthesis involving a new 327
aminotransfer reaction and its application to dibenzopentalene synthesis, Eur. J. 328
Org. Chem. (2011) 4885–4891;
329
(b) R. Leardini, D. Nanni, A. Tundo, G. Zanardi, Novel [3+2] radical annulations 330
of cyano-substituted aryl radicals with alkynes, Tetrahedron Lett. 39 (1998) 331
2441–2442.
332
Please cite this article in press as: T.M. Babar, et al., Synthesis of hexacyclic fused isocoumarin framework through selective domino
multicyclizations under catalyst and solvent free conditions, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.03.022