A novel one-pot pseudo five-component isocyanide-based reaction: Synthesis of 2,6-bis(alkylamino)-benzofuro[5,6-b]furan-4,8-dione derivatives

Article abstract of DOI:10.1016/j.tetlet.2012.10.072

A novel one-pot pseudo five-component reaction of isocyanides with 2,5-dihydroxycyclohexa-2,5-diene-1,4-dione and various aliphatic and aromatic aldehydes in ethanol at room temperature has been studied. 2,6-Bis(alkylamino)- benzofuro[5,6-b]furan-4,8-dion

Full text of DOI:10.1016/j.tetlet.2012.10.072

Tetrahedron Letters 53 (2012) 7085–7087
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Tetrahedron Letters
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A novel one-pot pseudo five-component isocyanide-based reaction: synthesis
of 2,6-bis(alkylamino)-benzofuro[5,6-b]furan-4,8-dione derivatives
⇑
Sajjad Keshipour, Shabnam Shaabani, Ahmad Shaabani
Department of Chemistry, Shahid Beheshti University, G. C., PO Box 19396-4716, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel one-pot pseudo five-component reaction of isocyanides with 2,5-dihydroxycyclohexa-2,5-diene-
1,4-dione and various aliphatic and aromatic aldehydes in ethanol at room temperature has been studied.
2,6-Bis(alkylamino)-benzofuro[5,6-b]furan-4,8-dione derivatives were isolated as the products in good
yields after 24 h.
Received 21 April 2012
Revised 5 October 2012
Accepted 18 October 2012
Available online 27 October 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Isocyanide
Benzofuran
Quinone
Multi-component
Natural and synthetic quinonoid compounds are well known.
They continue to demand attention by virtue of their presence in
antitumor quinone natural products such as (À)-saframycin1 and
rac-mitomycin.2,3 This category of compounds has a variety of bio-
logical properties such as antibacterial, antifungal, antiprotozoal,
inhibition of the human immunodeficiency virus (HIV)-1 reverse
transcriptase, and antitumor activity.4–9 Kendomycin [(À)-TAN
2162] A, a novel ansamycin compound has been shown to be a po-
tent endothelin receptor antagonist and an anti-osteoporotic com-
pound with remarkable antibacterial and cytostatic activity.10
Balsaminones A (B) and B (C) were isolated from the pericarp of
fruit of Impatiens balsamina L. and have significant antipruritic
activity11 (Fig. 1). Some of these pharmacological effects have been
attributed to the formation of DNA-damaging anion-radical inter-
mediates formed by bioreduction of the quinone nucleus.12
via the reaction of 2,5-dihydroxycyclohexa-2,5-diene-1,4-dione
(1), aldehydes 2, and isocyanides 3 in EtOH as the solvent at room
temperature (Scheme 1).
This chemistry permits us to introduce molecular diversity
under mild reaction conditions and to synthesize a large number
of 2,6-bis(alkylamino)-benzofuro[5,6-b]furan-4,8-dione deriv-
atives 4a–m.28 The reaction is straightforward and treatment of
2,5-dihydroxycyclohexa-2,5-diene-1,4-dione (1) (1 mmol) and
various aldehydes 2 (2 mmol) with isocyanides 3 (2 mmol) in EtOH
(10 mL) led to the formation of 4a–m (Fig. 2).
The structures of compounds 4a–m were deduced from their IR,
mass, elemental analyses, and 1H NMR spectral data. For example,
the 1H NMR spectrum of 4a consisted of a multiplet for the cyclo-
hexyl ring protons (d = 1.02–1.98), a broad signal for the NH–CH
cyclohexyl protons (d = 2.86), a broad singlet for the NH (d = 6.45)
protons, and two broad resonances for the aromatic protons
(d = 7.74 and 8.16). It is noteworthy that the 13C NMR spectra of
Furans are useful synthetic intermediates13–15 finding utility as
masked a
,b-unsaturated esters,16 and as precursors to hydroxypyr-
anones17 and polyoxygenated natural products18 as well as to
mono- and oligosaccharides.19 Furan substructures are an impor-
tant motif in materials chemistry providing promising plastics de-
rived from renewable sources,20 self-healing macromolecular
materials,21 conducting polymers,22 and photovoltaics.23 Hence,
the synthesis of furans has attracted considerable attention.24–26
As part of our continuing interest in the development of new
synthetic methods in heterocyclic chemistry and our interest in iso-
cyanide-based multi-component reactions (IMCRs),27 we describe
an efficient synthesis of fully substituted 2,6-bis(alkylamino)-
benzofuro[5,6-b]furan-4,8-dione derivatives 4a–m in high yields
O
O
O
OH
MeO
OX
O
B X= H
O
HO
OH
H
H
O
HO
C
X=
HO
HO
O
O
H
A
OH
H
H
⇑
Corresponding author. Tel.: +98 2129902800; fax: +98 2122431663.
E-mail address: a-shaabani@sbu.ac.ir (A. Shaabani).
Figure 1. Some biologically active quinones.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.072

7086
S. Keshipour et al. / Tetrahedron Letters 53 (2012) 7085–7087
O
attempts were made to transform the products into the corre-
sponding alcohols via electrochemical reduction, however they
were not reduced under these conditions. Such behavior has also
been reported for similar compounds,29 which are in accord with
our results and conclusions.
Although no mechanistic studies have been carried out, it is
conceivable that the initial event is the condensation between
the 2,5-dihydroxycyclohexa-2,5-diene-1,4-dione (1) and the alde-
hyde 2 providing intermediate 5. These are reactive species with
an o-quinone methide (oQM) scaffold.30 Then, on the basis of the
well-established chemistry of reactions of isocyanides with elec-
tron deficient heterodienes,31 the intermediates 5 may undergo a
[1+4] cycloaddition reaction with the isocyanides to produce inter-
mediate 6. Imine to enamine tautomerization produces compound
7, which then undergoes a comparable sequence to form the furan
on the other side scheme 2.
O
O
R
R'
NH
O
OH
O
EtOH
rt, 24 h
HN
R'
2
R'
N
C
2
O
R
H
HO
1
2
R
3
O
4a-m
R= aliphatic or aromatic
R'= cyclohexyl, 1,1,3,3-tetramethylbutyl or tert-butyl
Scheme 1. Synthesis of 2,6-bis(alkylamino)-benzofuro[5,6-b]furan-4,8-dione
derivatives 4a–m.
most of the products did not show any signals even after extended
scanning. For products 4e, 4g, and 4j signals were observed only for
the non-aromatic segment of the molecule. For example, the 13C
NMR spectrum of 4e exhibited four signals for the cyclohexyl rings
and the signals for the other C-atoms were not evident (see supple-
mentary data). More interestingly, the signals for the OMe groups,
as substituents on the phenyl rings, were also not observed. Appar-
ently, the presence of a free radical in the molecule and its reso-
nance within the aromatic systems caused major portions of the
13C NMR spectra associated with the aromatic systems and their
substituents to collapse. Attempts to record 13C NMR spectra of
the products using d-TFA and d5-pyridine also failed. Furthermore,
In summary, we have developed an efficient and potentially
useful novel reaction for the synthesis of 2,6-bis(alkylamino)-
benzofuro[5,6-b]furan-4,8-diones 4a–m. The products were
formed in good yields on mixing the readily available substrates
in ethanol as the solvent. The broad scope, operational simplicity,
practicality, and mild reaction conditions render this an attractive
NO2
Br
O
O
NO2
NH
O
O
O
O
O
O
HN
O2N
O
HN
NH
O
HN
NH
O
O
4c
4b
(83%)
(84%)
Br
4a
(81%)
OMe
NH
O2N
HN
S
O
O
O
OMe
NH
O
O
O
HN
MeO
NH
HN
O
O
O
O
O
O
4e
S
4d
(83%)
4f
(80%)
(87%)
MeO
HN
OMe
O
O
O
O
O
O
OH
NH
O
O
HN
NH
HN
NH
O
O
O
HO
O
O
O
4g
(89%)
4i
4h
(80%)
(82%)
NO2
MeO
O
O
O
O
O
O
HN
NH
HN
NH
HN
NH
O
O
O
O
4l
4k
(82%)
(83%)
4j
(81%)
OMe
O2N
O
O
HN
NH
O
4m
O
(84%)
MeO
Figure 2. The structures and isolated yields of products 4a–m.

S. Keshipour et al. / Tetrahedron Letters 53 (2012) 7085–7087
7087
O
O
O
O
O
O
OH
R'
O
O
O
O
-H2O
C
N
N
R
OH
R
H
2
HO
HO
HO
HO
H
3
R'
H
O
1
O
R'
R'
6
5
tautomerization
O
O
N
O
O
R'
1)
R
HN
O
O
R'
2) R
H
C
NH
R
NH
R
HO
O
R'
R'
O
7
4a-m
Scheme 2. Proposed mechanism for the formation of compounds 4a–m.
16. Yoshimura, F.; Sasaki, M.; Hattori, I.; Komatsu, K.; Sakai, M.; Tanino, K.;
Miyashita, M. Chem. Eur. J. 2009, 15, 6626–6644.
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1011.
approach for the generation of different 2,6-bis(alkylamino)-
benzofuro[5,6-b]furan-4,8-diones. This reaction may find use in
diversity-oriented synthesis and for the design of pharmaceutical
substance libraries.
19. Yu, X.; O’Doherty, G. De. Novo Synthesis in Carbohydrate Chemistry: From
Furans to Monosaccharides and Oligosaccharides. In Chemical Glycobiology;
Chen, X., Halcomb, R., Wang, P. G., Eds.; American Chemical Society:
Washington, DC, 2008; pp 3–28.
20. Gandini, A.; Silvestre, A. J. D.; Neto, C. P.; Sousa, A. F.; Gomes, M. J. Polym. Sci.,
Part A: Polym. Chem. 2009, 47, 295–298.
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Acknowledgments
We gratefully acknowledge financial support from the Iran Na-
tional Science Foundation (INSF) and the Research Council of Sha-
hid Beheshti University.
Supplementary data
24. Wong, H. N. C.; Hou, X.-L.; Yeung, K.-S.; Huang, H. Five-Membered
Heterocycles: Furan In Modern Heterocyclic Chemistry; Alvarez-Builla, J.,
Vaquero, J. J., Barluenga, J., Eds.; Wiley-VCH: Weinheim, Germany, 2011; Vol.
1, pp 533–592.
25. Sarvary, A.; Shaabani, S.; Shaabani, A.; Ng, S. W. Tetrahedron 2011, 67, 3624–
3630.
26. Teimouri, M. B.; Khavasi, H. R. Tetrahedron 2007, 63, 10269–10275.
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Rezayan, A. H.; Keshipour, S. Tetrahedron 2009, 65, 3492–3495; (d) Shaabani,
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Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
10.072.
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28. Typical procedure illustrated by the synthesis of 2,6-bis(cyclohexylamino)-3,7-
bis(4-nitrophenyl)benzofuro[5,6-b]furan-4,8-dione (4a). To a stirred solution
of 2,5-dihydroxycyclohexa-2,5-diene-1,4-dione (1) (1 mmol) and 4-
nitrobenzaldehyde (2) (2.1 mmol) in EtOH (10 mL), cyclohexyl isocyanide 3
(2.1 mmol) was added. The mixture was stirred for 24 h at room temperature.
After completion of the reaction (monitored by TLC), the solvent was removed
under vacuum and the residue purified by column chromatography using n-
hexane–EtOAc (1:4) as the eluant. The appropriate fractions were pooled and
the solvent removed by evaporation to give the product 4a as a black powder
(0.51 g, 81%); dec. >190 °C. IR (KBr) cmÀ1: 3319, 2930, 2855, 1700, 1669, 1516,
1347. 1H NMR (300.13 MHz, DMSO-d6) d: 1.02–1.98 (20H, m, 10CH2 of
cyclohexyl), 2.86 (2H, br s, 2CHNH), 6.45 (2H, br s, 2NH), 7.74 (4H, br s, CH-Ar),
8.16 (4H, br s, CH-Ar). 624 (M+, 5), 608 (5), 578 (5), 532 (5), 494 (5), 444 (10),
323 (55), 271 (60), 189 (30), 83 (70), 55 (100). Anal. Calcd for C34H32N4O8: C,
65.38; H, 5.16; N, 8.97. Found C, 65.39; H, 5.18; N, 8.99.
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