A novel three-component reaction of a secondary amine and a 2-hydroxybenzaldehyde derivative with an isocyanide in the presence of silica gel: an efficient one-pot synthesis of benzo[b]furan derivatives

Article abstract of DOI:10.1016/j.tetlet.2009.07.115

Reaction of an isocyanide with an iminium ion intermediate, formed by reaction between an electron-poor 2-hydroxybenzaldehyde derivative and a secondary amine in the presence of silica gel proceeds smoothly at room temperature to afford benzo[b]furan deri

Full text of DOI:10.1016/j.tetlet.2009.07.115

Tetrahedron Letters 50 (2009) 5625–5627
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel three-component reaction of a secondary amine
and a 2-hydroxybenzaldehyde derivative with an isocyanide in the presence
of silica gel: an efficient one-pot synthesis of benzo[b]furan derivatives
*
Ali Ramazani , Amir Tofangchi Mahyari, Morteza Rouhani, Aram Rezaei
Chemistry Department, Zanjan University, PO Box 45195-313, Zanjan, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 April 2009
Revised 9 July 2009
Accepted 17 July 2009
Available online 24 July 2009
Reaction of an isocyanide with an iminium ion intermediate, formed by reaction between an electron-
poor 2-hydroxybenzaldehyde derivative and a secondary amine in the presence of silica gel proceeds
smoothly at room temperature to afford benzo[b]furan derivatives in high yields.
Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
Keywords:
Silica gel
Multi-component reaction
Isocyanide
2-Hydroxy-5-nitro-benzaldehyde
2-Hydroxy-5-bromo-benzaldehyde
Secondary amine
Benzo[b]furan
Iminium ion
1. Introduction
tuted 2-formylaminocarboxamides.14,15 The reaction between sal-
icylaldehyde, isocyanides, and ammonium formate under Ugi
Multi-component reactions (MCRs) have attracted significant
attention in combinatorial chemistry.1 Of pivotal importance in
this area are the isocyanide-based MCRs such as the versatile Ugi
and Passerini reactions.1–4 The ability of isonitriles to undergo fac-
ile addition with a nucleophile and an electrophile under mild con-
ditions makes them useful reactants for the development of novel
MCRs.2,5 Isocyanides,6 regarded for many years as compounds with
unpleasant odor and very few chemical and pharmaceutical appli-
cations, are now looked upon as useful synthons with interesting
chemical properties. This change in attitude can be attributed pri-
marily to the renaissance of isocyanide-based multi-component
reactions (MCRs),7,8 for example, the Passerini three-component
reaction (P-3CR),9,10 and more importantly, the Ugi four-compo-
nent reaction (U-4CR),11,12 with its ability to deliver a wide vari-
ety13 of peptide analogs and heterocyclic compounds for
investigation in drug discovery programs.
four-component condensation conditions affords benzo[b]furan
derivatives in low yields.16
Furan derivatives, obtained from both synthetic and natural
sources, have attracted much interest due to their wide ranging
pharmaceutical applications.17–19 Many naturally occurring furans
show interesting biological activities, such as cytotoxic and antitu-
mor properties,19,20 as well as antispasmodic,21 antimicrobial,22,23
and several other potentially useful activities.24
2. Results and discussion
As part of our ongoing program to develop efficient and robust
methods for the preparation of heterocyclic compounds,25–30 we
report here a simple, one-pot, three-component reaction between
isocyanides 4, secondary amines 1, and an electron-poor 2-
hydroxybenzaldehyde derivative 2 in the presence of silica gel at
The well-known Ugi four-component condensation between
aldehydes, isocyanides, and ammonium formate affords N-substi-
ambient temperature, leading to benzo[b]furan derivatives
7
(Scheme 1 and Table 1). In the absence of silica gel, the yields were
only ca. 20% at room temperature after 24 h and in each case sev-
eral by-products were observed (based on TLC investigations). We
also used 2-hydroxybenzaldehyde and 2,5-dihydroxybenzalde-
hyde in this reaction, but the yields of the corresponding products
* Corresponding author. Tel.: +98 241 5152572; fax: +98 241 5283100.
E-mail address: aliramazani@yahoo.com (A. Ramazani).
0040-4039/$ - see front matter Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.115

5626
A. Ramazani et al. / Tetrahedron Letters 50 (2009) 5625–5627
O
R
Bn
Bn
R
N
N
O
X
OH
H
CH2Cl2, r.t., 30 min
1.
2.
silica gel
H
N
H
X
X
1
2
+
+
R
Bn
4
R1
N
,
-10 °C, 5min
C
OH
N
OH
R
silica gel
-H2O
4
2
R1
1
3
5
R
Bn
N
N
Bn
silica gel,
solvent-free conditions
R1
X
X
silica gel
tautomerism
NR1
NH
7
r.t., 24 h
O
O
6
7
Scheme 2. Proposed mechanism for the formation of benzo[b]furan derivatives 7 in
the presence of silica gel.
Scheme 1. Three-component synthesis of benzo[b]furan derivatives
presence of silica gel.
7 in the
amine 1 would give the iminium ion intermediate 3, which would
react with the alkyl isocyanide 4 to afford intermediate 5. The ionic
intermediate 5 would cyclize into benzofuran 6. Tautomerization
of 6 could then lead to formation of the benzo[b]furan derivatives
7.
7 were very low and in both cases several by-products were
observed (based on TLC). As indicated in Table 1, the reactions
proceeded efficiently with electron-withdrawing 2-hydroxybenz-
aldehyde derivatives 2 in the presence of silica gel; electron-releas-
ing 2-hydroxybenzaldehyde derivatives are not suitable starting
materials in these reactions. The high yields of 7a–j can be ex-
plained by the greater electrophilicity of carbonyl groups of elec-
tron-withdrawing 2-hydroxybenzaldehyde derivatives relative to
carbonyl groups of electron-releasing 2-hydroxybenzaldehyde
derivatives.
3. Conclusions
In conclusion, we have developed an efficient route for the one-
pot synthesis of benzo[b]furan derivatives 7 from simple and read-
ily available isocyanides 4, secondary amines 1, and electron-poor
salicylaldehydes 2 in the presence of silica gel. The ease of work-up
and high yields of products make this procedure a useful addition
to modern synthetic methods.
The structures of compounds 7a–j were deduced from their IR,
and high-field 1H and 13C NMR spectra, and their mass spectra. For
example, the IR spectrum of 7a showed a strong absorption at
3415 cmÀ1 indicating the presence of an amine. The 1H NMR spec-
trum of 7a consisted of one singlet for the methyl groups (CMe3,
d = 1.12), one singlet for the two methylenes (2 CH2 of two benzyls,
d = 4.21), an amine hydrogen atom (d = 4.07) which was exchange-
able with D2O, a multiplet for the aromatic protons (d = 7.21–7.37),
one doublet of doublets for the aromatic benzo[b]furan (C-4(H))
4. General Procedure
Compounds 7a–j; general procedure exemplified for 7a: A mix-
ture of dibenzylamine (0.19 mL, 1 mmol) and 2-hydroxy-5-nitro-
benzaldehyde (0.167 g, 1 mmol) in dry CH2Cl2 (5 mL) was stirred
at room temperature for 0.5 h. To this mixture, a solution of tert-
butyl isocyanide (0.12 mL, 1 mmol) in dry CH2Cl2 (2 mL) at
À10 °C was added rapidly and the solution was stirred for 5 min
at À10 °C. Subsequently, powdered silica gel (1 g) (Merck) was
added rapidly to the reaction mixture which was allowed to warm
to room temperature. The solvent was removed under reduced
pressure and the residue was allowed to stand for 24 h at room
temperature. Flash column chromatography of the residue using
petroleum ether-diethyl ether (10:1) as eluent, gave 7a as a red
viscous oil.
3
4
proton (d = 7.91, JHH = 6.5 Hz, JHH = 2.3 Hz), and a doublet for
the aromatic benzo[b]furan (C-6(H)) proton (d = 8.16,
4JHH = 2.3 Hz). The 1H decoupled 13C NMR spectrum of 7a showed
15 distinct resonances, the partial assignment of these resonances
is given below. The 1H and 13C NMR spectra of compounds 7b–j
were similar to those of 7a, except for the aromatic moieties and
the alkyl groups which exhibited characteristic signals with appro-
priate chemical shifts.
Although we have not established the mechanism of the reac-
tion in an experimental manner, a plausible reaction sequence that
accounts for the formation of 7 is shown in Scheme 2. Thus con-
densation of 2-hydroxybenzaldehyde derivative 2 and secondary
N,N-dibenzyl-N-[2-(tert-butylamino)-5-nitro-1-benzofuran-3-
yl]amine, 7a: Red viscous oil; yield: 90%. IR (KBr) (t
max, cmÀ1): 3415
(NH), 1646, 1523, 1453, 1346, 1215. 1H NMR (250 MHz, CDCl3) dH:
1.12 (9H, s, CMe3), 4.21 (4H, s, 2 CH2), 4.07 (1H, br s, NH, exchanged
by D2O addition), 7.21–7.37 (11H, m, H–Ar), 7.91 (1H, dd,
3JHH = 6.5 Hz,4JHH = 2.3 Hz, H-4, benzofuran), 8.16 (1H, d,
4JHH = 2.3 Hz, H-6, benzofuran). 13C NMR (62.5 MHz, CDCl3) dC:
29.93 (3 CH3 of CMe3), 52.45 (C of CMe3NH), 58.73 (2 CH2),
110.03, 111.89, 128.50 (3 CH, benzofuran), 104.68, 115.30,
152.07, 158.35 (4 C, benzofuran), 143.90 (C(NO2)), 127.37,
128.38, 129.16 (10 CH), 139.00 (2 Cipso). Anal. Calcd for
C26H27N3O3: C, 72.71; H, 6.34; N, 9.78. Found: C, 72.69; H, 6.32;
N, 9.75. MS (EI): m/z (%) = 429 (M+, 5), 338 (8), 282 (16), 106
(28), 91 (100), 57 (17), 41 (8).
Table 1
Synthesis of benzo[b]furan derivatives in the presence of silica gel
Product
R1
R
Xa
% Yieldb
7a
7b
7c
7d
7e
7f
7g
7h
7i
tert-Butyl
Cyclohexyl
1,1,3,3-Tetramethylbutyl
2,6-Dimethylphenyl
Benzyl
tert-Butyl
1,1,3,3-Tetramethylbutyl
tert-Butyl
1,1,3,3-Tetramethylbutyl
Cyclohexyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Methyl
Methyl
Benzyl
Benzyl
Benzyl
NO2
NO2
NO2
NO2
NO2
NO2
NO2
Br
90
86
94
91
80
84
90
85
88
80
Br
Br
7j
Acknowledgment
a
We also used 2-hydroxybenzaldehyde and 2,5-dihydroxybenzaldehyde in this
reaction, but the yields of the corresponding products 7 were very low and in both
cases several by-products were observed.
This work was supported by the ‘Iran National Science Founda-
tion: INSF’.
b
Isolated yields.

A. Ramazani et al. / Tetrahedron Letters 50 (2009) 5625–5627
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Supplementary data
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