An efficient and direct solvent-free synthesis of naphtho[1,2-b]furans, naphtho[2,1-b]furans, and furo[3,2-c]chromenes

Article abstract of DOI:10.1055/s-0029-1217736

An efficient and direct synthesis of naphtho[l,2b]furans, naphtho[2,1-b]furans, and furo[3,2-c]chromenes is described. Heating a mixture of a naphthol or 4-hydroxycoumarin, an isocyanide, and an aldehyde under an argon atmosphere and solvent-free conditio

Full text of DOI:10.1055/s-0029-1217736

2542
LETTER
An Efficient and Direct Solvent-Free Synthesis of Naphtho[1,2-b]furans,
Naphtho[2,1-b]furans, and Furo[3,2-c]chromenes
Synthesis of
N
aphtho[
1
e
,2-
b
]
furans
h
,
Naphtho[2,
d
1-
b
]furans,
a
i
ndFuro[3,2-
A
c
]chromenes dib,*a Mohammad Mahdavi,a Sharareh Bagherzadeh,a Hamid Reza Bijanzadehb
a
School of Chemistry, University College of Science, University of Tehran, PO Box 14155-6455, Tehran, Iran
Fax +98(21)66495291; E-mail: madib@khayam.ut.ac.ir
b
Department of Chemistry, Tarbiat Modarres University, PO Box 14115-175, Tehran, Iran
Received 9 February 2009
Abstract: An efficient and direct synthesis of naphtho[1,2-
b]furans, naphtho[2,1-b]furans, and furo[3,2-c]chromenes is de-
scribed. Heating a mixture of a naphthol or 4-hydroxycoumarin, an
isocyanide, and an aldehyde under an argon atmosphere and sol-
vent-free conditions afforded the title compounds in excellent
yields.
Key words: naphtho[1,2-b]furans, naphtho[2,1-b]furans, furo[3,2-
c]chromenes, isocyanides, three-component reactions, solvent-free
synthesis, cyclizations, heterocycles
In 2002, Nair et al. reported a three-component reaction
between 4-hydroxycoumarin, 4-hydroxypyrone, or 4-hy-
droxyquinolinone, cyclohexyl isocyanide, and aldehydes
in refluxing benzene to afford the corresponding annelat-
ed furans.14 However, their procedure has some draw-
backs such as long reaction times (12–24 h) and, in some
cases, fairly low yields of the products (down to 34%).
Furthermore, it cannot be extended to naphthols, which
are unreactive under the same reaction conditions.
Extended arenofurans have potential applications as fluo-
rescent dyes, probes and photosensitizers, organic light-
emitting diodes, two-photon absorption materials, sec-
ond- and higher-order nonlinear optics, and supramolecu-
lar structures.1–5
The naphthofuran nucleus is a key structural motif found
in some natural products such as ( )-laevigatin (1,
Figure 1).6 Several synthetic compounds containing a
naphthofuran scaffold have been shown to possess diverse
biological activities such as antifungal,7 antibacterial,8 an-
tiviral,9 b-adrenolytic,10 antitumor,11 and anthelmintic12
activity. 7-Methoxy-2-nitronaphtho[2,1-b]furan (2) is one
of the strongest mutagens described for mammalian
cells.13 The development of efficient syntheses of these
bioactive heterocycles has thus attracted many organic
and medicinal chemists for decades and continues to be an
active research area.
In 2006, an aminobenzofuran synthesis was reported from
a three-component reaction between phenols, aldehydes,
and isocyanides.14 This procedure involved formation of
Mannich adducts 3 from phenols or b-naphthol, an alde-
hyde, and N
SYNLETT 2009, No. 15, pp 2542–2544
x
x
.x
x
.2
0
0
9
Advanced online publication: 27.08.2009
DOI: 10.1055/s-0029-1217736; Art ID: D04709ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Naphthol[1,2-b]furans, Naphthol[2,1-b]furans, and Furo[3,2-c]chromenes
2543
Table 1 Synthesis of 2-Aminoarenofurans 7a–p
7
OH
Ar
R
Yield (%)a
7a
7b
7c
7d
7e
7f
a-naphthol
Ph
c-Hex
92
93
90
95
90
90
85
88
83
89
84
89
91
95
95
93
a-naphthol
Ph
t-Bu
a-naphthol
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
Ph
c-Hex
a-naphthol
t-Bu
a-naphthol
1,1,3,3-tetramethylbutyl
a-naphthol
c-Hex
7g
7h
7i
b-naphthol
c-Hex
b-naphthol
4-MeC6H4
3-MeC6H4
4-FC6H4
4-FC6H4
4-MeC6H4
Ph
t-Bu
b-naphthol
c-Hex
7j
b-naphthol
t-Bu
7k
7l
b-naphthol
c-Hex
b-naphthol
c-Hex
7m
7n
7o
7p
4-hydroxycoumarin
4-hydroxycoumarin
4-hydroxycoumarin
4-hydroxycoumarin
c-Hex
Ph
t-Bu
4-MeC6H4
4-MeC6H4
t-Bu
1,1,3,3-tetramethylbutyl
a Isolated yields.
4 h to 1 d for the aminofuran formation), fairly low yields
of the products (60–91% for the first step and 25–76% for
the second, and lower yields in a one-pot procedure with-
out isolation of the Mannich intermediate), and low atom-
economy.
NHR
O
Ar
OH
solvent-free
+
C–
+
+
R
N
ArCHO
argon, 180 °C, 1.5 h
4
5
6
7
In recent times, the progress in the field of solvent-free
reactions is gaining significance because of their high ef-
ficiency, operational simplicity, and environmentally be-
nign processes.15 As part of our continuing efforts on the
development of new routes for the preparation of biologi-
cally active heterocyclic compounds,16 we report herein
an efficient and direct synthesis of these bioactive hetero-
cycles via a one-pot and solvent-free reaction.
NHR
Ar
NHR
NHR
O
Ar
O
O
Ar
O
O
7m–p
7g–l
7a–f
Scheme 2
Thus a mixture of a-naphthol, b-naphthol, or 4-hydroxy-
coumarin 4, an aldehyde 5, and an isocyanide 6 underwent
a one-pot addition reaction under an argon atmosphere
and solvent-free conditions. The reaction proceeded at
180 °C and was complete within 1.5 hours to produce
N-alkyl-3-arylnaphtho[1,2-b]furan-2-amines 7a–f in 90–
95% yields, N-alkyl-3-arylnaphtho[2,1-b]furan-2-amines
7g–l in 83–89% yields, and N-alkyl-3-arylfuro[3,2-
c]chromenes 7m–p in 91–95% yields (Scheme 2,
Table 1).17 1H NMR analysis of the reaction mixtures
clearly indicated formation of the corresponding 2-amino-
arenofurans 7.
The structures of the isolated products 7 were deduced by
1
means of H NMR and 13C NMR spectroscopy and ele-
mental analysis.17
A mechanistic rationalization for this reaction is provided
in Scheme 3. The first step may involve condensation of
the enol 4 with the aldehyde and formation of enone inter-
mediate 8. Then [4+1] cycloaddition of this ortho-quino-
ne methide and the isocyanide 6 gives an iminolactone
intermediate 9, which tautomerizes to 2-aminofuran 7 un-
der the reaction conditions.
Synlett 2009, No. 15, 2542–2544 © Thieme Stuttgart · New York

2544
M. Adib et al.
LETTER
(12) (a) Ronto, G.; Grof, P.; Buisson, J. P.; Einhorn, J.;
Demerseman, P. Mutagenesis 1992, 7, 243. (b) Debnath,
A. K.; Hansch, C.; Kim, K. H.; Martin, Y. C. J. Med. Chem.
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(14) El Kaïm, L.; Grimaud, L.; Oble, J. Org. Biomol. Chem.
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Scheme 3
In conclusion, we have developed an efficient and direct
route for the preparation of naphtho[1,2-b]furans, naph-
tho[2,1-b]furans, and furo[3,2-c]chromenes of potential
synthetic, chemical, and pharmacological interest. Readi-
ly available substrates, simple experimental procedure,
excellent yields of the products, fairly short reaction
times, and environmentally friendly reaction conditions
characterize the present three-component reaction.
(16) (a) Adib, M.; Sayahi, M. H.; Ziyadi, H.; Zhu, L. G.;
Bijanzadeh, H. R. Synthesis 2008, 3289. (b) Adib, M.;
Sheibani, E.; Zhu, L. G.; Bijanzadeh, H. R. Synlett 2008,
2941. (c) Adib, M.; Mohammadi, B.; Bijanzadeh, H. R.
Synlett 2008, 3180. (d) Adib, M.; Mohammadi, B.;
Bijanzadeh, H. R. Synlett 2008, 177. (e) Adib, M.; Sayahi,
M. H.; Ziyadi, H.; Bijanzadeh, H. R.; Zhu, L. G.
Tetrahedron 2007, 63, 11135. (f) Adib, M.;Aali Koloogani,
S.; Abbasi, A.; Bijanzadeh, H. R. Synthesis 2007, 3056.
(g) Adib, M.; Sheibani, E.; Abbasi, A.; Bijanzadeh, H. R.
Tetrahedron Lett. 2007, 48, 1179. (h) Adib, M.; Sheibani,
E.; Mostofi, M.; Ghanbary, K.; Bijanzadeh, H. R.
Tetrahedron 2006, 62, 3435. (i) Adib, M.; Mahdavi, M.;
Mahmoodi, N.; Pirelahi, H.; Bijanzadeh, H. R. Synlett 2006,
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Acknowledgment
This research was supported by the Research Council of University
of Tehran as a research project (6102036/1/03).
(17)
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Synlett 2009, No. 15, 2542–2544 © Thieme Stuttgart · New York

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