Optimized synthesis and simple purification of 2,5-diamino-thiophene-3,4- dicarboxylic acid diethyl ester

Article abstract of DOI:10.1080/00397910701557432

A stable diamino thiophene was synthesized in high purity with a three-fold increase in yield over previous reports via simple crystallization using inexpensive reagents. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701557432

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Optimized Synthesis and Simple Purification
of 2,5‐Diamino‐thiophene‐3,4‐dicarboxylic
Acid Diethyl Ester
a
a
a
Marie Bourgeaux , Sophie Vomscheid & W. G. Skene
a
Department of Chemistry , University of Montreal , Montreal, Quebec,
Canada
Published online: 05 Oct 2007.
To cite this article: Marie Bourgeaux , Sophie Vomscheid & W. G. Skene (2007) Optimized Synthesis and
Simple Purification of 2,5‐Diamino‐thiophene‐3,4‐dicarboxylic Acid Diethyl Ester, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:20, 3551-3558, DOI:
10.1080/00397910701557432
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Synthetic Communications , 37: 3551–3558, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701557432
Optimized Synthesis and Simple
Purification of 2,5-Diamino-thiophene-3,4-
dicarboxylic Acid Diethyl Ester
Marie Bourgeaux, Sophie Vomscheid, and W. G. Skene
Department of Chemistry, University of Montreal, Montreal, Quebec,
Canada
Abstract: A stable diamino thiophene was synthesized in high purity with a three-fold
increase in yield over previous reports via simple crystallization using inexpensive
reagents.
Keywords: diamino thiophene, Gewald reaction, one-pot reaction
INTRODUCTION
Thiophenes constitute an interesting class of compounds that has attracted
much attention in the areas of organic synthesis and materials science alike.
Their synthetic appeal is due in part to their pharmaceutical properties,
[
1,2]
which include antiulcer and antiviral/antitumor properties,
other biological agents including human leukocyte elastases, allosteric
along with
[
3]
[
4]
[5]
enhancers, and nonpeptide antagonists, to name but a few. These proper-
ties have resulted in the preparation of many thiophene derivatives including
amino analogues, shown in Fig. 1, which are ideal precursors for new pharma-
[6]
ceutical products with high biological availabilities. Not only do thiophenes
possess desired pharmaceutical properties, they also exhibit outstanding pro-
perties suitable for functional materials such as organic light-emitting
[
7,8]
[9–13]
diodes
and field effect transistors.
These ideal properties stem from
Received in the USA September 26, 2006
Address correspondence to W. G. Skene, Department of Chemistry, University of
Montreal, Pavillon J.A. Bombardier, C.P. 6128, Succ. Centreville, Montreal, Quebec
H3C 3J7, Canada. E-mail: w.skene@umontreal.ca
3
551

3552
M. Bourgeaux, S. Vomscheid, and W. G. Skene
Figure 1. Mono- and diamino thiophene derivatives.
[
14,15]
their reversible oxidation
[
and their semiconductor-like behavior
in addition to their capacity to undergo
16]
obtained upon p-doping,
oxidative polymerization leading to conducting polymers.
[17–19]
Our interest in amino thiophenes stemmed from the finding that they are
useful precursors in the synthesis of conjugated functional materials via
[
20–30]
Schiff bases.
These novel materials are synthesized in a simple fashion
without any of the challenging reaction conditions or purification protocols
encountered with their vinylenic analogs. The ideal precursor for the Schiff
base materials is 3; however, it is extremely unstable and spontaneously decom-
poses under ambient conditions. For such reasons, 1 and 2 are suitable alterna-
tives for new functional materials owing to their electron-withdrawing groups,
which render them air stable. Although the synthesis of monoamino thiophenes
[
31–34]
(4 and 5)
dithiane-2,5-diol with either malononitrile or ethylcyano acetate,
consists simply of a Knoevenagel condensation from 1,4-
the
[3,4,31–39]
syntheses of the diamino precursors 1 and 2 are unfortunately not as trivial.
The synthesis of 1 is not only challenging because of its low yield (8%), but
it is also plagued with numerous purifications required to remove the
unreacted elemental sulfur with toxic solvents such as CS and multiple flash
2
[
40,41]
chromatography. Very little effort
the synthetic protocol of 1 and its derivatives beyond Gewald’s original
report
has focused on the optimization of
[
42,43]
(Scheme 1). This is particularly surprising given the pharmaceutical
importance of amino thiophenes. The long reaction times involving upward of 1
week and time-consuming multiple purification steps concomitant with residual
sulfur contamination unfortunately do not lend themselves to large-scale
pharmaceutical or functional materials productions. We therefore set out to
optimize the synthesis of 1 through judicious choice of reagent stoichiometry
Scheme 1. General synthetic scheme leading to 1.

Synthesis of Substituted 2,5-Diamino-thiophene
3553
and other parameters that would simplify its purification and increase the yield
while making the synthesis amenable to large-scale synthesis.
Previous examples of the Gewald reaction were done using copious
amounts of N,N-dimethylformamide (DMF) to dissolve the elemental sulfur
leading to homogeneous reaction conditions. As an alternative to these
methods, we first examined the use of ethanol as a suitable solvent for this
reaction because the excess volumes of DMF renders product isolation
extremely difficult and results in low yields. The reaction to afford 1 in
ethanol requires heating to sufficiently solubilize the elemental sulfur and to
drive the reaction. Even though 1 is highly stable at room temperature, it
decomposes upon heating. The effect of reaction temperature upon the
product formation was therefore examined according to Table 1. The
solvent amounts and the stoichiometries of the reaction were also studied.
The main advantage of this approach is the reduced number of polymeric
by-products, which in turn simplifies the purification because the product is
obtained in relatively high purity after one silica flash-chromatographic
column. Despite the easier purification, the desired product is still obtained
in only low yields.
Although the exact Gewald reaction mechanism is still unclear, it can be
rationalized according to that proposed in Scheme 2. The use of an organic
base to drive the reaction is evident from the proposed mechanism and the
general one shown in Scheme 1. The base is further required to digest the
allotrope S elemental sulfur and to make a reactive linear zwitterionic
8
[
44]
species.
This ring-opening process is further favored by polar solvents
such as DMF. However, the use of large volumes of this solvent is problematic
for product isolation. We therefore examined the Gewald reaction using
minimal amounts of DMF and various reagent stoichiometries as reported
in Table 2. As shown in entry 5, this method offers a means to manage the
amount of sulfur reagent and hence control the quantity of unreacted sulfur,
making for an easier purification. By pouring the reaction mixture into
water and then recrystallizing the filtered solid in a mixture of ethylacetate/
hexanes, 1 can be obtained easily in .98% purity, void of any sulfur contami-
nation. Furthermore, yields that are three times greater than previous reports
are possible by this method. The notable advantages of the present method-
ology are the mild reaction conditions, short reaction times, increased yield,
and purification by simple crystallization in ethylacetate/hexanes with no
multiple flash chromatography.
EXPERIMENTAL
All reagents were used as received from Aldrich without further purification.
Triethylamine was distilled under reduced pressure prior to use, whereas
anhydrous DMF was obtained from a GlassContour solvent purification
system. The reported melting point is uncorrected.

a
Table 1. Effect of reaction temperature and time, concentration, and stoichiometry upon the yield of 1 using absolute ethanol as the solvent
Ethylcyano
acetate
(equivalents)
Reaction
temperature
(8C)
Sulfur
(equivalents)
NHEt
(equivalents)
2
Reaction
time (h)
b
EtOH (mL)
c
Entry
Yield 1 (%)
1
2
1
1
1
1
1
1
1
1
2
1
1
150
150
150
150
130
150
75
Reflux
80
80
2.5
2
,1
1
1.2
1
d
3
1
2
,1
1
4
5
6
7
8
2
1
45
45
2.5
16
2.5
2
3
10
1
0
2
45
45
1
2
1
3
2
1
75
45
2
3
a
The reactions were performed using 1 g of sulfur without any additional conditions other than those reported in the table.
Absolute ethanol.
b
c
Isolated yield either by crystallization in ethylacetate/hexanes or by silica flash chromatography.
d
Addition of CS to digest any unreacted sulfur.
2

Synthesis of Substituted 2,5-Diamino-thiophene
3555
Scheme 2. Proposed mechanism for the Gewald reaction of 1.
General Procedure
The optimized general procedure for the synthesis of 1 is the following.
Elemental sulfur (1 g, 31.2 mmol) was added to DMF (5 mL) along with
ethylcyanoacetate (7.12 g, 62.3 mmol) and triethylamine (1 mL, 7.1 mmol)
and then stirred at room temperature for 60 h. The resulting slurry was
a
Table 2. Effects of stoichiometry and reaction times upon the yield and purity of 1
Ethylcyano
acetate
Sulfur
Entry (equivalents) (equivalents) (equivalents) time (h)
Et
3
N
Reaction
Purity
c
(%)
b
Yield
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
1
0.5
0.5
0.5
1
0.5
0.5
18
48
48
60
60
60
60
60
0
14
12
22
24
0.2
22
17
—
,80
85
0.5
0.5
—
98
1
0.25
0.05
0.25
0.25
1
,50
94
1
0.5
—
a
The reactions were performed at room temperature using 1 g of sulfur in 5 mL of
DMF. See the experimental description for more details.
b
Isolated yield after crystallization in ethylacetate/hexanes.
The purity of the crystallized samples was measured by NMR using tert-butyl
benzene as an internal standard in deuterated acetone and by elemental analysis.
c

3556
M. Bourgeaux, S. Vomscheid, and W. G. Skene
filtered and then poured into water (125 mL). The resulting precipitate was
filtered, and the product (1.94 g, 24%) was obtained as yellow needles upon
recrystalization from a mixture of ethylacetate/hexanes. Mp: 155–1568C.
1
H NMR (acetone-d ): d ¼ 6.17 (s, 2H), 4.12 (q, 4H, J ¼ 7.1 Hz), 1.27
6
1
3
(
t, 6H, J ¼ 7.0 Hz). C NMR (DMSO-d6): d ¼ 165.6, 148.9, 104.5, 60.4,
14.8. Analytically calculated for C H N O S (258.30): C, 46.50; H, 5.46;
N, 10.85; O, 24.74; S, 12.41. Found: C, 46.57; H, 5.46; N, 10.65; S, 12.44.
10 14 2 4
EI-MS: m/z 258.1 ([M]þ, 80%), 212 ([M-C2H5O]þ, 100%).
ACKNOWLEDGMENTS
The authors acknowledge financial support in part from the Natural Sciences
and Engineering Research Council Canada, Canada Foundation for Inno-
vation, Fonds de Recherche sur la Nature et les Technologies, and the
Centre for Self-Assembled Chemical Structures. M. B. thanks the Universite´
de Montr e´ al for a graduate scholarship, and S. V. thanks Le Minist e` re des
´
Affaires Etrang e` res for a travel grant.
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