Synthesis of 2-imino-3-aminobenzofurans via multicomponent reactions from TosMIC

Article abstract of DOI:10.1055/s-0030-1259325

A simple synthesis of 2-imino-3-aminobenzofurans was developed based on multicomponent reactions from p-toluenesulfonylmethylisocyanide, salicylaldehyde, and substituted anilines. The crystal structures of two of the aminobenzofurans were established by X-ray crystal structure analysis.

Full text of DOI:10.1055/s-0030-1259325

308
LETTER
Synthesis of 2-Imino-3-aminobenzofurans via Multicomponent Reactions
from TosMIC
S
ynthesis of 2-Imino-3
a
-aminoben
.
zofurans Carmen García-González,a Eduardo González-Zamora,*a Rosa Santillan,b Norberto Farfánc
a
Departamento de Química, Universidad Autónoma Metropolitana-Iztapalapa, San Rafael Atlixco 186, Col. Vicentina Iztapalapa,
México D. F. 09340, México
Fax +52(55)58044666; E-mail: egz@xanum.uam.mx
Departamento de Química, Centro de Investigación y de Estudios Avanzados del IPN, Apdo. Postal 14-740, México D. F. 07000, México
Facultad de Química, Departamento de Química Orgánica, Universidad Nacional Autónoma de México, México D. F. 04510, México
b
c
Received 30 August 2010
component reactions (U-3CR, and U-4CR).5 This meth-
odology has been applied to the synthesis of structurally
diverse molecules,5 including benzofuran derivatives.6
Thus, the reaction between phenols, aldehydes, and isocy-
anides affords 2-aminobenzofurans in a one-pot process
via Mannich adducts;7 2-alkylamino- and 2-arylamino-
3[(2-hydroxybenzylidene)amino]benzofurans can be gen-
erated from salicylaldehyde, isocyanides, and ammonium
formate,6a and 2,3-diaminobenzofurans can be obtained
using electron-poor 2-hydroxybenzaldehyde derivates,
isocyanides, and secondary amines.8
Abstract: A simple synthesis of 2-imino-3-aminobenzofurans was
developed based on multicomponent reactions from p-toluenesulfo-
nylmethylisocyanide, salicylaldehyde, and substituted anilines. The
crystal structures of two of the aminobenzofurans were established
by X-ray crystal structure analysis.
Key words: multicomponent reactions, imines, furans, TosMIC,
isocyanide
To date, several synthetic routes to aminobenzofurans
have been reported. Among the earlier examples, the syn-
thesis of 2,3-diaminobenzofurans 1a (Figure 1) using an
excess of salicylaldehyde, concentrated ammonia, and
aqueous potassium cyanide can be mentioned.1 Later,
Harhash prepared several 2-amino-3-arylamino-
benzofurans2 by treatment of Schiff bases with potassium
cyanide in acetic acid followed by reaction with salicyl-
aldehyde in the presence of catalytic amounts of piperi-
dine. Also, 3-aminobenzofurans 1b have been
synthesized from 2,6-dimethylmorpholine, salicylalde-
hyde, and terminal acetylenes in the presence of copper(I)
iodide3 or the Cu(OTf)2–CuCl-catalyzed coupling of sali-
cyladehyde derivatives with alkynylsilanes and secondary
amines followed by intramolecular cyclization.4
In continuation with these studies, involved a multicom-
ponent reaction, we envisioned the one-pot synthesis of
benzofurans from the condensation of p-toluenesulfonyl-
methyl isocyanide (TosMIC) with salicylaldehyde and
anilines by means of MCR. The later compounds are of
interest and pharmacological importance due to their po-
tential applications as anticonvulsant, anti-inflammatory,9
antitumor,10 and antimycobacterial11 agents, they have
also been shown to inhibit b-fibril formation.12
The present methodology provides selectively 2-imino-3-
aminobenzofurans 5a–f from a 2-hydroxybenzaldehyde
(2), an amine 3, and p-toluenesulfonylmethyl isocyanide
(4, Scheme 1), in a one-pot process under mild reaction
conditions in 39–71% yield,13 adding a new derivative
to the list of the formidable van Leusen reaction which
provides a broad diversity of heterocycles, such as
oxazoles,14 imidazoles,14,15 indoles,16 triazoles,17 and pyr-
roles.18
R2
O
O
N
HO
R1
N
N
The 1H NMR and 13C NMR spectra evidenced the forma-
tion of the new heterocycle; selected spectroscopic data
OH
O
1b
Table 1 Selected 1H, 13C NMR (ppm), and IR (cm–1) Data for Com-
pound 5a–f
1a
R1 = H, NO2, Cl, Br
2 = H, Cl, Br
R
Compound 1H NMR (H-7) 13C NMR (C-7) IR (C=N)
Yield (%)
Figure 1
5a
5b
5c
5d
5e
5f
8.98
9.04
9.00
9.05
9.05
8.94
156.2
155.0
156.2
155.9
155.8
154.1
1595
1599
1590
1595
1600
1604
61
61
69
58
39
71
A different approach is the isocyanide-based multicompo-
nent reactions (IMCR) that comprise the Passerini three-
component reaction (P-3CR), and the Ugi three- and four-
SYNLETT 2011, No. 3, pp 0308–0310
x
x.
x
x.
2
0
1
1
Advanced online publication: 19.01.2011
DOI: 10.1055/s-0030-1259325; Art ID: S05510ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 2-Imino-3-aminobenzofurans
309
HO
1
O
7
NC
O
R4
R3
5
H2N
O
2
O
N
+
+
2
MeOH
S
4
3
R1
OH
R4
R3
refluxed
HN
R2
R1
4
2
3
R2
R1
OH
H
R2
H
H
H
H
H
NO2
R3
R4
Yield (%)
5a–f
5a
5b
5c
5d
5e
5f
NO2
NO2
NO2
NO2
OMe
H
H
H
Cl
H
H
H
61
61
69
58
39
71
OH
OMe
NO2
H
Scheme 1 Synthesis of 2-imino-3-aminobenzofurans
Figure 2 X-ray molecular structures and perspective view of compounds 5a and 5c
are summarized in Table 1. All of the compounds showed with the second molecule of 2-hydroxybenzaldehyde (2)
a low field signal around d = 9.00 ppm attributed to H-7 yields the new heterocycle 5.
that correlates with the 13C NMR around d = 156.0 ppm.
In conclusion, a simple MCR is described for the synthe-
The IR spectra revealed absorptions characteristic for
sis of 2-imino-3-aminobenzofurans from three compo-
N=C group from 1590–1604 cm–1. Accordingly, the N–
C2 fragment derived from TosMIC remains in the final
product incorporating two molecules of aldehyde and
amine.
nents by coupling of salicylaldehyde with various amines
and p-toluenesulfonylmethyl isocyanide. The process is
easy and demonstrates the versatility of isocyanide-based
multicomponent reactions providing a different route to
The structures of 5a and 5c were corroborated by X-ray the existing conventional synthesis.
diffraction (Figure 2). Both compounds crystallized in the
space group C2/c of the monoclinic system.19
Supporting Information for this article is available online at
A possible reaction sequence that accounts for the forma-
http://www.thieme-connect.com/ejournals/toc/synlett.
tion of the 2-imino-3-aminobenzofurans is depicted in
Scheme 2. Condensation of 2-hydroxybenzaldehyde (2)
Acknowledgment
with aminophenol 3 gives the Schiff base 6. Subsequent
attack of the TosMIC anion 7 gives the intermediate 8
which undergoes van Leusen reaction pathway to give the
Financial support from CONACYT and a scholarship for M.C.G. is
acknowledged. Also we thank J. A. Zamudio for fruitful comments
intermediate 9,15 tautomerization of 9 followed by nucleo- and referee 1 for comments and suggestions in the mechanism.
philic attack of phenolic OH will result in the formation of
11. Elimination of TsH, as is common in the van Leusen
reaction, will generate the benzofuran 12, which on hy-
(1) Baldwin, J. E.; Blythin, D. J.; Waight, E. S. J. Chem. Soc. C
drolysis affords the intermediate 13. Finally, the amine 13
References and Notes
1969, 735.
Synlett 2011, No. 3, 308–310 © Thieme Stuttgart · New York

310
Ma. C. García-González et al.
LETTER
R4
R3
R2
R4
R3
H2N
R1
Ar
Ts
NC
O
N
N
+
NC
Ts
H
+
R1
OH
OH
OH
R2
6
2
3
NH
OH
7
H
N
Ar
O
Ar
Ar
Ar
N
N
H
N
N
van Leusen
reaction
NC
tautomerism
H
Ts
NH
Ts
Ts
Ts
OH
Ar
OH
9
8
10
11
Ar
Ar
NH
N
NH
H2O
2
N
NH
NH2
– CH2O
O
O
O
HO
Scheme 2 Proposed mechanism
(2) Harhash, A. H.; El-Bannani, A. A. Z. Naturforsch., B: Chem.
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yield, mp 253–255 °C. IR: 3366 (OH), 1595 (C=N), 1310,
1275, 744 cm–1. 1H NMR (400 MHz, DMSO-d6): d = 11.52
(1 H, br s, OH), 10.78 (1 H, br s, OH), 8.98 (1 H, s, H-7), 8.44
(1 H, br s, NH), 7.71–7.67 (2 H, m, ArH), 7.60–7.56 (2 H, m,
ArH), 7.42–7.32 (3 H, m, ArH), 7.24 (1 H, t, J = 7.6 Hz,
ArH), 6.93–6.87 (2 H, m, ArH), 6.61 (1 H, d, J = 9.04 Hz,
ArH). 13C NMR (100 MHz, DMSO-d6): d = 160.0, 156.2
(C=N), 151.0, 147.4, 144.8, 141.7, 138.4, 134.1, 132.1,
126.7, 126.4, 123.7, 120.7 (2 C), 120.1, 117.9, 117.2, 114.5,
111.9, 111.7, 109.2. MS (20 eV): m/z (%) = 389 (100) [M]+,
372 (16), 342 (8), 268 (27), 236 (13), 211 (25), 122 (38).
HRMS: m/z calcd for C21H16N3O5 [M+ + H]+: 390.1084;
found: 390.1083.
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(19) Crystallographic data: Single crystal X-ray diffraction
studies were realized on a KAPPA CCD diffractometer.
Solution and refinement: direct methods SHELXS-8620 and
SIR-200421 for structure solution and the SHELXL-9722
software package for refinement and data output. For
compounds 5a and 5c full crystallographic data were
submitted as CIF files with the Cambridge Crystallographic
Data Centre, CCDC Nos. 750840 for 5a and 750841 for 5c.
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(13) General Procedure for the Preparation of 2-Imino-3-
aminobenzofurans
Salicylaldehyde 2 (2.00 mmol) was added to a solution of the
amines 3a–f (1.00 mmol) in MeOH (15 mL). The mixture
was stirred for 30 min at r.t. and p-toluenesulfonylmethyl
isocyanide (4, 1.20 mmol) was added. The reaction mixture
was refluxed (3–24 h), and the solid precipitate was
collected by filtration and washed with hexane.
Selected Data for Compound 5a
The product 5a (0.450 g) was obtained as a red solid in 61%
Synlett 2011, No. 3, 308–310 © Thieme Stuttgart · New York

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