emission properties can be tailored by reacting the amine.
Also, by changing the electron density of the amine,
dramatic fluorescence changes occur, making primary
amino fluorophores interesting in situ reaction sensors.
Unfortunately, primary aminothiophenes are highly un-
stable and few aminobithiophenes are known.18
Stable 2-aminothiophenes can be prepared, provided
they contain an electron-withdrawing group in the 3-posi-
tion, possible via the Gewald reaction.19,20 Despite the
extensive use of this reaction for preparing pharmacologi-
cally relevant 2-aminothiophenes, 2-aminobithiophene de-
rivatives have not been reported. We were therefore incited
to prepare such derivatives, especially conjugated
push-pull aminobithiophenes for achieving highly fluor-
escent and stable bithiophenes. The preparation of de novo
conjugated aminobithiophenes 1-5 and their cursory
spectroscopic characterization are herein presented.
and oxidization with elemental sulfur. The advantage of
the Gewald reaction is that the desired 2-aminothiophenes
are prepared in one pot and can be isolated by standard
purification methods. Moreover, the products are air
stable and do not require inert atmospheres for handling.
The unsaturated aldehyde precursor required for the
Knoevenagel condensation was obtained in 61% yield by
the rearrangement of thienyloxirane by adding trimethyl-
sulfonium iodide to 2-thiophene carboxaldeyde.21 2-Thie-
nylacetaldehyde was immediately used without isolation
and purification by combining it with ethyl cyanoacetate,
elemental sulfur, and diethylamine (DEA) in ethanol and
stirredatroom temperature. The resulting 1 was isolated as
a solid in 25% overall yield for the combined steps and was
stable under ambient conditions. Although higher yields of
the Gewald reaction are expected with malononitrile ow-
ing to the symmetric Knoevenangel intermediate formed,
the advantage of ethyl cynanoacetate is that the ester of 1
can be readily modified. This provides a handle to both
tailor the solubility and covalently link the prefluorophore
to other substrates. Nonetheless, the yield of 1 is consistent
for the Gewald reaction.22
Scheme 1. Synthesis of 1-5
The nitro function is highly complementary to the
2-amino group of 1, resulting in a strong electronic
push-pull system. Addition of the nitro group was done
by standard nitration in trifluoroacetic anhydride (TFAA)
and nitric acid to afford 3. An aldehyde was also selected as
an alternate electron-withdrawing group for preparing the
targeted highly fluorescent fluorophore, given that the
nitro group is known to quench the fluorescence in certain
fluorophores. The aldehyde group was introduced into 1
by Vilsmeier-Haack formylation. 2 was isolated in 41%
yield after removal of the amine protecting N,N-dimethyl
imine group by acidic hydrolysis. The protecting group is
formed by condensation between the amine and DMF
catalyzed by the acid generated by decomposition of the
POCl3 in situ. Although the terminal functional groups in 2
couldpotentiallycondenseleading toSchiff basepolymers,
no such autocondensation products were observed. This is
most likely owing to the collective electronic effects of the
two groups that deactivate both the amine and aldehyde,
preventing autocondensation. The preparation of both
push-pull fluorophores is summarized in Scheme 1.
Product identification of 1-5 was done according to
standard methods (see Supporting Information). Structur-
al confirmation of 2 was additionally done by X-ray
crystallography. Suitable X-ray quality crystals were
grown by evaporation inacetone. The molecule crystallizes
in a monoclinic P21/c space group with four molecules per
lattice. The resolved crystal confirmed the correct structure
for the compound, as seen in Figure 1. It is evident that the
heteroatoms orient themselves ina syn arrangement, which
is uncommon for bithiophenes.23 Meanwhile, the
The preliminary step involved in the Gewald19,20 reac-
tion is the Knoevenagel condensation of activated cynano
methylenes such as ethyl cyanoacetate or malononitrile
with R-methylene carbonyl compounds catalyzed by sec-
ondary and tertiary amines. This is followed by cyclization
(18) Myung-Hwa, K.; Chun-Ho, P. Novel Thienopyridine Deriva-
tives or Pharmaceutically Acceptable Salts Thereof, Process For the
Preparation Thereof and Pharmaceutical Composition Comprising the
Same. World Patent WO /2007/102679, August 13th 2007. Ibrahim,
M. A.; Lee, B. G.; Park, N. G.; Pugh, J. R.; Eberl, D. D.; Frank, A. J. Synth.
Met. 1999, 105, 35.
(19) Gewald, K. Chem. Ber. 1965, 98, 3571–3577.
(20) Gewald, V. K.; Kleinert, M.; Thiele, B.; Hentschel, M. J. Prak.
Chem. 1972, 314, 303–314.
ꢀ
(21) Lemini, C.; Ordonez, M.; Perez-Flores, J.; Cruz-Almanza, R.
Synth. Commun. 1995, 25, 2695–2702.
(22) Buchstaller, H.-P.; Siebert, C. D.; Lyssy, R. H.; Frank, I.;
Duran, A.; Gottschlich, R.; Noe, C. R. Monatsh. Chem. 2001, 132, 279.
(23) Chaloner, P. A.; Gunatunga, S. R.; Hitchcock, P. B. Acta
Crystallogr., Sect. C 1994, 50, 1941–1942.
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