1592
LETTER
A Novel Four-Component Reaction for the Synthesis of 2,5-Diaminofuran
Derivatives
S
ynthesis of 2,5-D
b
iaminofuran
d
D
erivatives olali Alizadeh,*a Sadegh Rostamnia,a Mao-Lin Hub
a
Department of Chemistry, Tarbiat Modarres University, P.O. Box 14115-175, Tehran, Iran
Fax +98(21)88006544; E-mail: aalizadeh@modares.ac.ir
b
School of Chemistry and Materials Science, Wenzhou University, Wenzhou 325027, P. R. of China
Received 7 March 2006
Although the trapping of the 1:1 intermediate formed
between dialkyl acetylenedicarboxylates and isocyanides
with O–H, N–H, and C–H acids has been studied in detail
by a number of research groups,5–9 trapping of the initially
formed 1:1 intermediate with carboxylic acids has not
been reported.
Abstract: A facile synthesis of highly functionalized 2,5-diamino-
furan derivatives by the multicomponent reaction of tert-butyl
isocyanide and dialkyl acetylenedicarboxylates in the presence of
2-phenylacetic acid or 2,2-diphenylacetic acid is described.
Key words: alkyl isocyanide, dialkyl acetylenedicarboxylate, ali-
phatic carboxylic acid, multicomponent reaction
We wish to report a simple one-pot four-component
reaction between dialkyl acetylenedicarboxylates and
tert-butyl isocyanide in the presence of 2-phenylacetic
acid or 2,2-diphenylacetic acid leading to highly function-
alized diaminofuran derivatives 3.
With regard to green chemistry, atom-efficient trans-
formations of readily available starting materials into
complex organic building blocks become increasingly im-
portant.1 Here, multicomponent coupling reactions which
directly yield the desired products via domino or tandem
reaction sequences offer significant advantages over step-
wise procedures.2 Multicomponent reactions (MCRs)
provide a powerful tool towards the one-pot synthesis of
diverse and complex compounds on the one hand and
small and ‘drug-like’ heterocycles on the other hand. No
other single synthesis technology enables chemists to
search such large chemical spaces as provided by MCRs.
MCRs that involve isocyanides are by far the most versa-
tile reactions in terms of scaffolds and number of accessi-
ble compounds. A number of advantages make MCRs
very popular in the community of combinatorial chemists:
superior atom economy, simple procedures, the one-pot
character, and the high and ever increasing number of
accessible backbones.
The reactions of tert-butylisocyanide with dialkyl acetyl-
enedicarboxylates 1 in the presence of 2-phenylacetic acid
or 2,2-diphenylacetic acid 2 undergo a smooth 2:1:1 addi-
tion reaction in dichloromethane at ambient temperature,
to produce highly functionalized diaminofuran deriva-
tives 3 in 80–98% yields (Table 1).
The structures of compounds 3a–g were deduced from
their elemental analyses, their IR, and high-field 1H NMR
and 13C NMR spectra. The mass spectrum of 3a displayed
a molecular ion (MC) peak at m/z = 444, which is consis-
tent with the 1:2:1 adduct of dimethyl acetylenedicarbox-
ylate, tert-butyl isocyanide, and 2-phenylacetic acid. The
1H NMR spectrum of 3a exhibited four single sharp lines
readily recognized as arising from tert-butyl group (d =
1.36 and 1.39 ppm), methoxy (d = 3.79, and 3.84) protons
along with an AX system (JAX = 16.0 Hz) for two methyl-
ene (d = 3.52, 3.67 ppm) protons. A fairly broad singlet
(d = 6.91 ppm) is observed for the NH group, and phenyl
moiety gave rise to characteristic signals in the aromatic
region of the spectrum. The 1H decoupled 13C NMR spec-
trum of 3a showed 18 distinct resonances in agreement
with the aminofuran structure. Finally, 3f was further
elucidated by single crystal X-ray diffraction analysis
(Figure 1).10
Polysubstituted furans play an important role in organic
chemistry not only due to their presence as key structural
units in many natural products3 and in important pharma-
ceuticals,4 but they can also be employed in synthetic
chemistry as building blocks. For this reason, the syn-
thesis of polysubstituted furans continues to attract the
interest of many synthetic chemists.
In the context of our ongoing studies on heterocyclic con-
struction mediated by zwitterionic intermediates,5 the
possibility of trapping the 1:1 intermediate formed be-
tween dialkyl acetylenedicarboxylate and isocyanides
with suitable O–H acids appeared attractive from the
viewpoint of devising a novel MCR.6
Although we have not established the mechanism of the
reaction between the isocyanides and the acetylenic esters
in the presence of aliphatic carboxylic acid derivatives 2
in an experimental manner, a possible explanation is
proposed in Scheme 1.
On the basis of the well-established chemistry of isocya-
nides,11–16 it is reasonable to assume that the functional-
ized diaminofuran 3 results from initial addition of the
isocyanide to the acetylenic ester and subsequent proton-
ation of the 1:1 adduct 4 by compound 2, followed by
SYNLETT 2006, No. 10, pp 1592–1594
Advanced online publication: 12.06.2006
DOI: 10.1055/s-2006-941581; Art ID: D07006ST
© Georg Thieme Verlag Stuttgart · New York
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