A regioselective synthesis of pentacyclic compounds containing coumarin, pyrrole, indene without catalysts under microwave irradiation

Article abstract of DOI:10.1016/j.cclet.2016.04.009

A concise and efficient approach was developed for the synthesis of pentacyclic compounds containing coumarin, pyrrole, indene in a regioselective manner in good yields via the reactions of N-substituted 4-aminocoumarin compounds and ninhydrin using micro

Full text of DOI:10.1016/j.cclet.2016.04.009

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Chinese Chemical Letters xxx (2016) xxx–xxx
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Chinese Chemical Letters
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Original article
A regioselective synthesis of pentacyclic compounds containing
coumarin, pyrrole, indene without catalysts under microwave
irradiation
*
Zhi-Wei Chen , Jun-Bo Hou, Zhao-Ran Dai, Xiao-Feng Yang
Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang
University of Technology, Hangzhou 310014, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A concise and efficient approach was developed for the synthesis of pentacyclic compounds containing
coumarin, pyrrole, indene in a regioselective manner in good yields via the reactions of N-substituted 4-
aminocoumarin compounds and ninhydrin using microwave irradiation. No catalysts are required in our
protocol.
Received 2 March 2016
Received in revised form 25 March 2016
Accepted 6 April 2016
Available online xxx
ß 2016 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Keywords:
4-Aminocoumarin
Catalyst-free
Ninhydrin
Regioselective
Annulation
1. Introduction
Pd(II)-catalyzed oxidative annulation of 4-aminocoumarin with
internal alkynes [6].
Coumarin derivatives are regarded as a structurally important
class of naturally occurring common compounds and exhibiting a
wide range of biological and pharmacological activities [1]. The
chromeno[3,4-b]pyrrol-4(3H)-one scaffold defines the structural
Polycyclic compounds with indeno-moieties appropriately
substituted on the pyrrolidine ring are an important class of
heterocycles, some of which exhibit potent pharmacological
properties [7]. In addition, appropriately substituted indenopyr-
rolidines have been shown to be potent inhibitors of angiotensin
converting enzyme (ACE) [8] and evaluated as antagonists of the
NMDA receptor [9].
The pharmacologically and biologically importance of chro-
meno[4,3-b]pyrrol-4(1H)-ones and appropriately substituted
indenopyrrolidines has stimulated the construction of pentacyclic
compounds containing coumarin, pyrrole, indene derivatives and
led us to generate a new set of dihydroxy chromenoindeno[2,1-
d]pyrrol analogs. Furthermore, to the best of our knowledge, only
one reference exists concerning dihydroxy chromenoindeno[2,1-
d]pyrrol-ones synthesis. Recently, Pradhan reported on a metallic
catalyst, tin oxide (SnO2) quantum dot (QD), and catalytic protocol
for the synthesis of 6b,11b-dihydroxy-6b,7,11b,12-tetrahydro-6H-
chromeno[4,3-b]indeno[2,1-d]pyrrol-6-ones [10]. We report here
the synthesis of 6b,11b-dihydroxy-12-substituted-6b,7,11b,12-
tetrahydro-6H-chromeno-[4,3-b]indeno[2,1-d]pyrrol-6-ones by a
regioselective method with good yields via the reactions of N-
substituted 4-aminocoumarin compounds and ninhydrin without
any catalysts utilizing microwave heating.
core of lamellarin
D and ningalin B, which exhibit potent
pharmacological properties including antitumour activity, HIV-1
integrase inhibition, multidrug resistance (MDR) reversal and
anadlgesic activity [2]. This type of core structure is one of the most
important precursors for the antibiotic martinelline, often found in
novel drug candidates [3]. Microwave heating has certain benefits
compared with conventional heating, such as reaction rate
acceleration, lower energy usage and formation of cleaner
products, i.e., fewer impurities, consequently microwave-assisted
organic synthesis has received a widespread attention [4]. In the
past several years, our group and others have developed various
protocols that can easily provide access to multifunctionalized
chromeno[4,3-b]pyrrol-4(1H)-one derivatives from readily avail-
able starting materials of chemical and pharmaceutical interest [5].
For example, Wang and his co-workers have developed a new
protocol for the synthesis of chromeno[4,3-b]pyrrol-4(1H)-ones by
*
Corresponding author.
E-mail address: chenzhiwei@zjut.edu.cn (Z.-W. Chen).
http://dx.doi.org/10.1016/j.cclet.2016.04.009
1001-8417/ß 2016 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Z.-W. Chen, et al., A regioselective synthesis of pentacyclic compounds containing coumarin, pyrrole,
indene without catalysts under microwave irradiation, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.04.009

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Table 2
2. Experimental
Synthesis of various substituted dihydrochromenoindeno [1,2-b]pyrroles.a
R2
Melting points were determined using a Bu¨chi B-540 capillary
melting point apparatus. The Microwave reactor was CEM Discover
908010 with IR-monitored temperature control. Recorded 1H NMR
and 13C NMR were obtained on a Varian instrument at 400 and
100 MHz, respectively, with TMS as the internal standard. Mass
spectra were measured with Thermo Finnigan LCQ-Advantage
instrument, and high resolution mass spectral (HRMS) data were
R1
R1
HO
O
O
O
HN
O
N
R2
OH
OH
catalyst-free
+
O
O
OH
O
1
2
3
Entry
R1
R2
Time
Products
Yield
(%)b
acquired on
techniques.
a Bruker micrOTOF-Q II instrument using ESI
(min)
1
2
ꢀC6H5
H
45
50
45
48
48
50
55
40
40
40
40
40
40
40
40
40
3a
3b
3c
3d
3e
3f
85
73
78
78
80
75
70
92
90
90
92
91
78
88
78
88
87
90
2.1. General procedure for the preparation of 4-(n-butylamino)-2H-
chromen-2-one
4-FC6H4
H
3
4-ClC6H4
4-BrC6H4
2-ClC6H4
2-CH3CO2C6H4
2,4-diClC6H3
2-MeC6H4
2-C2H5C6H4
2-MeOC6H4
4-MeC6H4
4-C2H5C6H4
4-MeOC6H4
Bn
H
4
H
5
H
A mixture of 4-hydroxycoumarin (0.01 mol) and n-butylamine
(0.02 mol) was stirred for 6 h in 50 mL of ethoxyethanol at reflux.
The solvent was then evaporated under vacuum and the crude
product was rinsed with diethyl ether to obtain pure 4-(n-
butylamino)-2H-chromen-2-one.
6
H
7
H
3g
3h
3i
8
H
9
H
10
11
12
13
14
15
16
17
18
H
3j
H
3k
3l
H
2.2. General procedure for the preparation of 4-(phenylamino)-2H-
chromen-2-one
H
3m
3n
3o
3p
3q
3r
H
n-Bu
H
4-ClC6H4
4-ClC6H4
H
ꢀMe
A
mixture of 4-hydroxycoumarin (0.01 mol) and aniline
ꢀC(CH3)3
40
40
(0.05 mol) was stirred at 185 8C for 45 min. The resulting mixture
was dissolved in methanol (20 mL) and the solution treated with
0.1 molar aqueous sodium hydroxide (40 mL) under stirring. After
30 min, the resulting precipitate was collected and recrystallized
from ethanol to obtain pure 4-(phenylamino)-2H-chromen-2-one.
H
a
All the reactions were performed with 1 (1 mmol), 2 (1 mmol) in toluene (7 mL)
by microwave heating at 110 8C.
b
Isolated yields based on 1.
2.3. General procedure for the preparation of
dihydrochromenoindeno [1,2-b]pyrroles
3. Results and discussion
Substituted 4-aminocoumarin (1) (1 mmol), ninhydrin (2)
(1 mmol), and toluene (7 mL) were introduced into a 10 mL
initiator microwave reaction vial. Subsequently, the reaction vial
was closed, stirred for 15 s, then the reaction mixture was stirred at
110 8C for 45 mins under microwave irradiation using a CEM
Discover microwave reactor The reaction was monitored by TLC.
After completion of the reaction, the reaction mixture was cooled
to r.t. The crude product was collected by filtration. The pure
product was obtained by recrystallization from ethanol.
Initially, we conducted this synthesis by reacting 4-phenyla-
mino coumarin (1a) with ninhydrin (2) to serve as the model to
establish the optimal condition. The various attempts are
summarized in Table 1. Taking solubility of reactants into
consideration, we initially utilized polar protic solvents, such as
MeOH, EtOH, MeCN and glycol. We investigated the model reaction
under catalyst-free conditions as well as with catalysts such as
AcOH, KHSO4, p-TSA.
In the preliminary experiment, the reaction was performed in
methanol at 60 8C with AcOH as catalyst and yielded a trace of 3a
(Table 1, entry 1). The reaction scarcely proceeded to give the
desired product, even at enhanced temperatures. Subsequently,
Table 1
Optimization of the reaction conditions.a
O
O
O
O
O
+
OH O
OH
OH
N
HN
O
Ph
HO
Ph
1a
2
3a
Entry
Solvent
Catalyst
Loading
(mol%)
Temp.
Time
Yield
(%)b
(8C)
(min)
1
2
MeOH
AcOH
AcOH
AcOH
AcOH
AcOH
p-TSA
KHSO4
AcOH
AcOH
none
10
10
10
10
10
10
10
20
40
0
60
78
90
90
90
45
60
70
50
55
60
45
trace
30
EtOH
3
MeCN
80
35
90
4
Toluene
Glycol
110
170
110
110
110
110
110
5
40
6
Toluene
Toluene
Toluene
Toluene
Toluene
60
7
80
8
88
90
9
10
90
a
All the reactions were performed with 1a (1 mmol), 2 (1 mmol), and solvent
(7 mL).
b
Isolated yields based on 1a.
Fig. 1. X-ray crystallographic analysis of the product 3b.
Please cite this article in press as: Z.-W. Chen, et al., A regioselective synthesis of pentacyclic compounds containing coumarin, pyrrole,
indene without catalysts under microwave irradiation, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.04.009

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3
O
O
O
O
O
O
O
O
O
OH O
O
O
O
OH
OH
H
path A
O
N
O
O
O
NH
Ar
N
HO
NH
Ar
Ar
Ar
II
I
3
1a
O
O
OH
O
O
OH
O
O
OH
O
O
H
O
path B
N
N
NH
Ar
NH
O
I
Ar
O
O
Ar
Ar
HO
O
O
O
1a
II
3*
Scheme 1. Proposed mechanism.
the reaction was repeated many times in different solvents, such as
MeCN, toluene and glycol and afforded the product, yields 30%,
35%, 90% and 40%, respectively (entries 2–5). Toluene provided a
higher yield than other organic solvents, therefore toluene was
chosen as the solvent for further reactions. The addition of
catalysts such as p-TSA, KHSO4, however, did not improve the
yields of the product (entries 6 and 7).
reaction of the amino group with one of the carbonyl group,
resulting in the formation of product 3.
The reason for the regioselectivity of this transformation is that
only the single regioisomer (3) is detected. The regiosomer (3*)
could arise from the interaction of the N-substituted 4-amino-
coumarin compound with one of the edge carbonyls of the
indanetrione, followed by hydride migration and intramolecular
cyclization (Scheme 1, Path B). Furthermore, the structure of 3
shows the both hydroxyl groups in a cis-relationship, confirmed by
X-ray structure of compound 3b in Table 2, which is explicable by
spatial restrictions imposed, generated by the annulation of
intermediate II. The spatial restrictions can orient the addition
of the arylamino group on one of the carbonyls from the side
opposite to the originally generated hydroxyl group.
Next, the model reaction was studied in toluene using different
amounts of AcOH and found that higher amounts of AcOH did not
increase the yield significantly (Table 1, entries
8 and 9).
Interestingly when this reaction was carried out with 1 mmol of
each reactant in 7 mL of toluene in the absence of catalysts at
110 8C under microwave irradiation for 45 min, a maximum yield
of 90% of the product 3a was obtained (Table 1, entry 10). The pure
product was obtained as a pale yellow solid by recrystallization
from ethanol.
4. Conclusion
With the optimized conditions in hand, we next decided to
ascertain the scope and generality of this method by using various
readily available starting materials. The results are presented in
Table 2. As usual, the reactions can be finished in 40–55 min. A
range of valuable substituted dihydrochromenoindeno [1,2-
b]pyrroles can be synthesized in good yields. We found that
reactants may not only be N-arylenaminones (R1, entries 2–4)
which possess electron-withdrawing substituents such as fluoro,
chloro and bromo groups at the para-position of the benzene ring,
but also analogs (R1, entries 8–13) having electron-donating
substituents such as methyl, ethyl and methoxyl groups which
gave the corresponding dihydrochromenoindeno [1,2-b]pyrroles
derivatives 3h–m in good yields. In addition to N-aryl substitu-
tents, N-aliphatic groups and 6-aliphatic groups were also found to
be suitable and provide the corresponding dihydrochromenoin-
deno[1,2-b]pyrroles derivatives in 78%–90% yields of the products
(Table 2, entries 14–17).
In conclusion, this investigation describes a facile and precise
protocol for the synthesis of a series of novel dihydrochrome-
noindeno [1,2-b]pyrroles in good yields via the reaction of
substituted 4-aminocoumarin and ninhydrin in an equimolar
ratio in the absence of catalysts at 110 8C. The simple work-up
procedure without column chromatographic purification, the
absence of catalysts, and the excellent yields of products render
this method particularly attractive. As shown in this investigation,
the reactions have high regioselectivity and one C–C and one C–N
bond formed in a single synthetic operation.
Acknowledgments
We are grateful to the National Natural Science Foundation of
China (No. 21276237) for financial support. Cooperation of our
colleagues in analytical research and development is highly
appreciated.
This protocol confirms the great scope of functionalities, such as
fluoro, chloro and bromo, which intimates the potential opportu-
nity of their further chemical exploitation and utilization. The
various structures of products were in accord with 1H NMR and 13
C
Appendix A. Supplementary data
NMR and mass spectral data. The structure of 3b was further
confirmed by X-ray crystallographic analysis (Fig. 1). The detail
data has been deposited in Table S1 in Supporting information.
On the basis of the above results together with the related
Supplementary material related to this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.cclet.2016.04.009.
reports [11–13],
a plausible mechanistic pathway for the
References
formation of the product is proposed in Scheme 1. This
transformation arises from the initial nucleophilic addition of
N-substituted 4-aminocoumarin compounds to ninhydrin lead-
ing to intermediate I. The N-substituted 4-aminocoumarin
compounds presumably add chemoselectively over the more
electrophilic middle carbonyl of the indanetrione (Scheme 1,
Path A), which is in equilibrium with its hydrate, ninhydrin.
Intermediate I undergoes successive imine–enamine tautomer-
ization to furnish intermediate II, followed by annulation via the
[1] (a) R.J. Anderson, D.J. Faulkner, C.H. Cun, et al., Metabolites of the marine
prosobranch mollusk Lamellaria sp., J. Am. Chem. Soc. 107 (1985) 5492–5495;
(b) N. Lindquist, W. Fenical, G.D. Van Duyne, et al., New alkaloids of the lamellarin
class from the marine ascidian Didemnum chartaceum, J. Org. Chem. 53 (1988)
4570–4574;
(c) H. Kang, W. Fenical, A.-D. Ningalins, Novel aromatic alkaloids from a western
Australian ascidian of the genus Didemnum, J. Org. Chem. 62 (1997) 3254–3262;
(d) S. Stanchev, G. Momekov, F. Jensen, et al., Synthesis, computational study and
cytotoxic activity of new 4-hydroxycoumarin derivatives, Eur. J. Med. Chem. 43
(2008) 694–706;
Please cite this article in press as: Z.-W. Chen, et al., A regioselective synthesis of pentacyclic compounds containing coumarin, pyrrole,
indene without catalysts under microwave irradiation, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.04.009

G Model
CCLET-3672; No. of Pages 4
4
Z.-W. Chen et al. / Chinese Chemical Letters xxx (2016) xxx–xxx
(e) S. Sardari, Y. Mori, K. Horita, etal., Synthesis and antifungal activity of coumarins
and angular furanocoumarins, Bioorg. Med. Chem. 7 (1999) 1933–1940.
[2] (a) J. Ham, H. Kang, A novel cytotoxic alkaloid of lamellarin class from a marine
ascidian Didemnum sp., Bull. Korean Chem. Soc. 23 (2002) 163–166;
(b) Z.H. Sui, J.H. Guan, M.J. Macielag, et al., Synthesis and biological activities of
novel b-carbolines as PDE5 inhibitors, Bioorg. Med. Chem. 13 (2003) 761–765;
(c) S.A. Yamashkin, L.G. Yudin, A.N. Kost, Synthesis of pyrroloquinolones, Chem.
Heterocycl. Compd. 19 (1983) 401–405;
(d) H. Fan, J.N. Peng, M.T. Hamann, et al., Lamellarins and related pyrrole-derived
alkaloids from marine organisms, Chem. Rev. 108 (2008) 264–287.
[3] D. Pla, A. Marchal, C.A. Olsen, et al., Modular total synthesis of lamellarin D, J. Org.
Chem. 70 (2005) 8231–8234.
[6] S.Y. Peng, L. Wang, J.Y. Huang, et al., Palladium-catalyzed oxidative annulation via
C–H/N–H functionalization: access to substituted pyrroles, Adv. Synth. Catal. 335
(2013) 2550–2557.
[7] (a) D.W. Brown, P.R. Graupner, M. Sainsbury, et al., New antioxidants incorpo-
rating indole and indoline chromophores, Tetrahedron 47 (1991) 4383–4408;
(b) J.A. Butera, S.A. Antane, B. Hirth, et al., Synthesis and potassium channel
opening activity of substituted 10H-benzo and furo[3,2-b]indole- and 5,10-dihy-
dro-indeno[1,2-b]indole-1-carboxylic acids, Bioorg. Med. Chem. Lett. 11 (2001)
2093–2097.
[8] (a) S. Hanessian, U. Reinhold, M. Saulnier, et al., Probing the importance of spacial
and conformational domains in captopril analogs for angiotensin converting
enzyme activity, Bioorg. Med. Chem. Lett. 8 (1998) 2123–2128;
(b) M.A. Ondetti, D.W. Cushman, Inhibition of the renin–angiotensin system. A
new approach to the therapy of hypertension, J. Med. Chem. 24 (1981) 355–361;
(c) J.A. Robl, M.P. Cimarusti, L.M. Simpkins, et al., Peptidomimetic synthesis: a
novel, highly stereoselective route to substituted freidinger lactams, J. Am. Chem.
Soc. 116 (1994) 2348–2355.
[4] (a) L. Perreux, A. Loupy, A tentative rationalization of microwave effects in
organic synthesis according to the reaction medium and mechanistic consider-
ations, Tetrahedron 57 (2003) 9199–9223;
(b) P. Lidstrom, J. Tierney, B. Wathey, et al., Microwave assisted organic synthesis
– a review, Tetrahedron 57 (2001) 9225–9283;
(c) D. Bogdal, J. Pielichowski, A. Boron, New synthetic method of aromatic
ethers under microwave irradiation in dry media, Synth. Commun. 28 (1998)
3029;
(d) J. Westman, An efficient combination of microwave dielectric heating and
the use of solid-supported triphenylphosphine for Wittig reactions, Org. Lett. 3
(2001) 3745–3747.
[9] S. Hayashibem, S. Yamasaki, N. Shiraishi, et al., Fused Indane Compound, WO
2009069610, 2009.
[10] K. Pradhan, S. Paul, A.R. Das, Synthesis of indeno and acenaphtho cores containing
dihydroxy indolone, pyrrole, coumarin and uracil fused heterocyclic motifs under
sustainable conditions exploring the catalytic role of the SnO2 quantum dot, RSC
Adv. 5 (2015) 12062–12070.
[5] (a) Z.W. Chen, Q. Zhu, W.K. Su, A novel sulfonic acid functionalized ionic liquid
catalyzed multicomponent synthesis of 10,11-dihydrochromeno[4,3-b]chro-
mene-6,8(7H,9H)-dione derivatives in water, Tetrahedron Lett. 52 (2011);
(b) Z.W. Chen, J.H. Bi, W.K. Su, Synthesis and antitumor activity of novel coumarin
derivatives via a three-component reaction in water, Chin. J. Chem. 31 (2013)
507–514;
[11] S. Muthusaravanan, C. Sasikumar, B.D. Bala, et al., An eco-friendly three-compo-
nent regio- and stereoselective synthesis of highly functionalized dihydroin-
deno[1,2-b]pyrroles under grinding, Green Chem. 16 (2014) 1297–1304.
[12] B. Jiang, Q.Y. Li, S.J. Tu, et al., Three-component domino reactions for
selective formation of indeno[1, 2-b]indole derivatives, Org. Lett. 14 (2012)
5210–5213.
(c) Z.W. Chen, X.F. Yang, W.K. Su, An efficient protocol for multicomponent
synthesis of functionalized chromeno[4, 3-b]pyrrol-4(1H)-one derivatives, Tetra-
hedron Lett. 56 (2015) 2476–2479.
[13] A. Abdolali, Z. Ameneh, R. Atieh, A novel and one-pot multicomponent approach to
the synthesis of dihyroindeno[1, 2-b]pyrroles and indeno[20,10:4,5]pyrrolo[1,2-a]-
fused 1,3-diazaheterocycles, Synthesis 3 (2011) 497–501.
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indene without catalysts under microwave irradiation, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.04.009