The development of a one pot, regiocontrolled, three-component reaction for the synthesis of thieno[2,3-c]pyrroles

Article abstract of DOI:10.1039/c3ob27492f

A three-component reaction has been developed that allows the regioselective synthesis of thieno[2,3-c]pyrroles. The reaction is based on the ability of 2-acetyl-3-thiophenecarboxaldehyde to react with amine and thiol nucleophiles to produce the corresponding tri-substituted thieno[2,3-c]pyrroles, with water as the only by-product. The developed reaction expands the range of synthetically accessible, tri-substituted thieno[2,3-c]pyrroles. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob27492f

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
COMMUNICATION
The development of a one pot, regiocontrolled, three-
component reaction for the synthesis of thieno[2,3-c]-
pyrroles†
Cite this: Org. Biomol. Chem., 2013, 11,
2932
Received 23rd December 2012,
Accepted 19th March 2013
Cynthia M. Hong and Alexander V. Statsyuk*
DOI: 10.1039/c3ob27492f
www.rsc.org/obc
A three-component reaction has been developed that allows the
regioselective synthesis of thieno[2,3-c]pyrroles. The reaction is
based on the ability of 2-acetyl-3-thiophenecarboxaldehyde to
react with amine and thiol nucleophiles to produce the corres-
ponding tri-substituted thieno[2,3-c]pyrroles, with water as the
only by-product. The developed reaction expands the range of
synthetically accessible, tri-substituted thieno[2,3-c]pyrroles.
Thienopyrroles are isosteric and isoelectronic to indoles, and
have unique electronic properties. Due to their unique stereo-
electronic properties, thienopyrroles find numerous appli-
cations in the areas of medicinal chemistry and molecular
electronics,1 and are of interest to both synthetic and theoreti-
cal chemists.2 Multiple methods for the synthesis of thieno-
[2,3-b], thieno[3,2-b], and thieno[3,4-b]pyrroles exist;3 however,
synthetic access to thieno[2,3-c]pyrroles remains limited. The
parent thieno[2,3-c]pyrrole scaffold has been prepared, yet the
synthesis of substituted thieno[2,3-c]pyrroles to tune the func-
tional properties of this scaffold remains a challenge. Known
methods of synthesis of thieno[2,3-c]pyrroles are linear, and
do not provide flexibility to rapidly install multiple substitu-
ents on the thieno[2,3-c]pyrrole scaffold.4 To this end, multi-
component reactions are the best suited for the rapid, green,
and atom economical synthesis of polysubstituted com-
pounds,5 yet multi-component reactions for the synthesis of
thieno[2,3-c]pyrroles have not been extensively studied.
Scheme 1 Three-component reaction of arylogous 1,4-dicarbonyl compounds
with amine and thiol nucleophiles.
Here, we report the development of a novel, one-pot,
modular, three-component reaction that creates tri-substituted
thieno[2,3-c]pyrroles under mild and simple reaction con-
ditions in a regiocontrolled manner that produces water as the
only by-product (Scheme 1). The reaction is based on the
ability of o-phthalaldehyde to react with thiols and amines to
Department of Chemistry, Center for Molecular Innovation and Drug Discovery,
Chemistry of Life Processes Institute, Silverman Hall, Northwestern University,
Evanston, IL 60208, USA. E-mail: a-statsyuk@northwestern.edu;
Fax: +1 847-491-7713; Tel: +1 847-467-1875
Scheme 2 (A) Reaction of 2,3-thiophenedicarboxaldehyde 5 with thiols and
amines. (B) Reaction of 2-acetylthiophene-3-carboxaldehydes 3a and 3b with
thiols and amines.
†Electronic supplementary information (ESI)
available. See DOI:
10.1039/c3ob27492f
2932 | Org. Biomol. Chem., 2013, 11, 2932–2935
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Communication
produce intensely fluorescent isoindoles with quantitative model substrate for our studies, because the reaction of thio-
yields.6
phene-2,3-dicarboxaldehyde 5 with β-mercaptoethanol and
Although the reaction of o-phthalaldehyde 1 with thiols and 4′-aminoacetophenone had been reported previously with the
amines is extensively used in analytical chemistry, the syn- formation of one regioisomeric thieno[2,3-c]pyrrole, but with
thetic potential of this reaction has been neglected due to the little exploration on the substrate scope.7 Unfortunately, the
inherent instability of the resulting isoindoles. Because thieno- reaction of thiophene-2,3-dicarboxaldehyde 5 with ethanol-
[2,3-c]pyrroles are known to be stable, we decided to explore amine and β-mercaptoethanol led to the formation of an inse-
the utility of this reaction in their synthesis. We decided to use parable mixture of two regioisomeric thieno[2,3-c]pyrroles 6
commercially available thiophene-2,3-dicarboxaldehyde 5 as a and 7 (Scheme 2A, data not shown), which severely limited the
Table 1 Substrate scope of the three-component reaction
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 2932–2935 | 2933

View Article Online
Communication
Organic & Biomolecular Chemistry
synthetic potential of this reaction. To eliminate the formation
of this regioisomeric mixture of 6 and 7, we replaced thio-
phene-2,3-dicarboxaldehyde 5 with regioisomeric 2-acetylthio-
phene-3-carboxaldehyde 3a and 3-acetylthiophene-2-carb-
oxaldehyde 3b, hoping that only one thieno[2,3-c]pyrrole
product would be formed (Scheme 2B). Both these compounds
can be easily synthesized in a two-step synthetic sequence on
the gram scale. We expected a significant decrease in the reac-
tivity of acetyl-thiophene-carboxaldehydes 3a and 3b towards
thiols and amines due to the reduced reactivity of the ketone
group; however much to our delight we observed reactions
between 3a and 3b with ethanolamine and β-mercaptoethanol
to form solely thieno[2,3-c]pyrrole products 8a and 8b with
88% and 65% yields, respectively (Scheme 2B). Thus, in con-
trast to thiophene-2,3-carboxaldehyde 5, 2-acetyl-thiophene-
3-carboxaldehyde 3a and 3-acetyl-thiophene-2-carboxaldehyde
3b allow full regiocontrol of this three-component reaction.
To survey the compatibility of common organic functional
groups with this three-component reaction, we treated
2-acetyl-thiophene-3-carboxaldehyde 3a with commercially
available and functionally diverse primary thiols and amines
(Table 1). We have found that the reaction is compatible with a
wide range of functional groups such as carboxylic acids, pyri-
dines, tertiary amines, indoles, phenols, amides, alcohols, and
esters. The reaction can also proceed under neat reaction con-
ditions (compounds 8a, and 20).8 Isopropylamine, however,
turned out to be a poor substrate for the reaction, giving 22%
yield of the corresponding thieno[2,3-c]pyrrole 35.9 All thieno-
[2,3-c]pyrroles that were made are stable compounds and
can be stored at −20 °C for at least six months without
decomposition.
Scheme 3 Reaction of 2-acetylthiophene-3-carboxaldehyde 3a with carbon
and phosphite nucleophiles.
Consideration of the reaction mechanism and the potential
involvement of the reactive imine/iminium intermediates
suggested that nucleophiles other than thiols could be
explored with this three-component reaction.
Scheme 4 Proposed mechanism scheme for the three-component reaction.
We turned our attention to the well-known Mannich and
Kabachnik–Fields reactions, which involve the reaction of eno-
lizable ketones and phosphite nucleophiles with reactive
iminium intermediates to generate the corresponding β-amino
ketone and phosphonate products, respectively.10 Treatment of
acetylacetone with 2-acetylthiophene-3-carboxaldehyde 3a in
the presence of ethanolamine under neat reaction conditions
led to the formation of the corresponding thieno[2,3-c]pyrrole
29 in 77% yield. Diethyl phosphite, however, was less reactive
and the reaction mixture required heating to produce the corres-
ponding thieno[2,3-c]pyrrolephosphonate 30 with 25% yield
(Scheme 3). To increase the yield, Mg(ClO4)2 was used as a
catalyst.11
Conclusions
In summary, we reported the development of a novel three-
component reaction for the synthesis of thieno[2,3-c]pyrroles
from readily available acetylthiophene carboxaldehydes,
amines, thiols, sp3-carbon, and phosphite nucleophiles that
provides rapid access to tri-substituted thieno[2,3-c]pyrrole
scaffolds under simple, mild, one-pot reaction conditions with
high yields. Water is the only byproduct of the reaction, and
the reaction can be run solvent free, which makes this reaction
environmentally friendly.
The developed three-component reaction is compatible
with a wide range of functional groups commonly used in
organic synthesis, thus allowing access to a wide variety of
functionally diverse thieno[2,3-c]pyrroles. The resulting substi-
tuted thieno[2,3-c]pyrroles can be used for drug discovery pur-
poses or as monomers in the synthesis of conducting
polymers.1 Investigations on the reaction mechanism, further
explorations of the reaction scope with other heterocyclic
ketoaldehydes to provide access to other types of c-annulated
Based on previous mechanistic studies,6 we rationalize that
the reaction mechanism of the reported reaction may involve
the formation of the imine/iminium intermediate from the
corresponding amine and 2-acetyl-thiophene-3-carboxaldehyde
3a, followed by 1,2-addition of thiol, carbon, or phosphorus
nucleophiles, subsequent cyclization, and water elimination
steps to produce thieno[2,3-c]pyrrole reaction products 34
(Scheme 4).
2934 | Org. Biomol. Chem., 2013, 11, 2932–2935
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Communication
pyrroles,12 and applications will be disclosed in the near
future.
J. Org. Chem., 1964, 29, 2160; (c) S. Soth, M. Farnier and
C. Paulmier, Can. J. Chem., 1978, 56, 1429;
(d) H. Hemetsberger and D. Knittel, Monatsh. Chem., 1972,
103, 194; (e) R. S. Gairns, C. J. Moody and C. W. Rees,
Acknowledgements
J.
Chem.
Soc.,
Chem.
Commun.,
1985,
1818;
(f) K. Srinivasan, K. G. Srinivasan, K. K. Balasubramanian
and S. Swaminathan, Synthesis, 1973, 313; (g) D. Wensbo,
U. Annby and S. Gronowitz, Tetrahedron, 1995, 51, 10323;
(h) D. J. Lee, K. Kim and Y. J. Park, Org. Lett., 2002, 4, 873.
4 (a) C. K. Sha and C. P. Tsou, J. Chem. Soc., Chem. Commun.,
1986, 310; (b) C. K. Sha and C. P. Tsou, J. Org. Chem., 1990,
55, 2446–2450; (c) G. W. Gribble, E. T. Pelkey and
F. L. Switzer, Synlett, 1998, 1061; (d) N. Ono, H. Hironaga,
K. Simizu, K. Ono, K. Kuwano and T. Ogawa, J. Chem. Soc.,
Chem. Commun., 1994, 8, 1019; (e) N. Ono, H. Hironaga,
K. Ono, S. Kaneko and T. Murashima, J. Chem. Soc., Perkin
Trans. 1, 1996, 417; (f) S.-M. Yang and J.-M. Fang, J. Org.
Chem., 1999, 64, 394.
5 A. Domling, W. Wang and K. Wang, Chem. Rev., 2012, 112,
3083.
6 P. Zuman, Chem. Rev., 2004, 104, 3217.
7 (a) M. A. El-borai, E. A. Aly and S. S. Gerges, Phosphorus,
Sulfur Silicon Relat. Elem., 1995, 101, 9; (b) M. A. El-Badawi,
Org. Chem.: Indian J., 2006, 2(5–6), 121–126.
Financial support for this work has been provided by North-
western University. Alexander V. Statsyuk is a Pew Scholar in
the Biomedical Sciences, supported by the Pew Charitable
Trusts. Frederick D. Lewis, Karl A. Scheidt, and Regan
J. Thomson are gratefully acknowledged for useful
discussions.
Notes and references
1 (a) D. W. Beight, J. M. Morin and J. S. Sawyer,
E. C. R. Smith (Eli Lilly, Indianapolis, IN) WO 2002012249,
2002; (b) A. J. Barker, J. G. Kettle and A. W. Faull (Zeneca
Ltd, UK) WO 9940914, 1999; (c) A. M. Birch, A. D. Morley
and A. Stocker, P. R. O. Whittamore (Astrazeneca) WO
2003074532, 2003; (d) J. C. Arnould (Astrazeneca) WO
2004018479, 2004; (e) B. Attenni, J. I. M. Hernando,
S. N. F. Malancona, J. M. Ontoria and M. Rowley (Istituto di
Ricerche di Biologia Molecolare P Angeletti S.p.A., Italy)
WO 2005023819, 2005; (f) J. B. Blair, D. Marona-Lewicka,
A. Kanthasamy, V. L. Lucaites, D. L. Nelson and
8 ESI.†
9 ESI.†
D. E. Nichols, J. Med. Chem., 1999, 42, 1106; (g) G. Balaji, 10 (a) M. Arend, B. Westermann and N. Risch, Angew. Chem.,
A. M. Della Pelle, B. C. Popere, A. Chandrasekaran and
S. Thayumanavan, Org. Biomol. Chem., 2012, 10, 3455.
Int. Ed., 1998, 37, 1044; (b) N. S. Zefirov and E. D. Matveeva,
ARKIVOC, 2008 (i), 1–17. Retrieved 2009-12-08.
2 (a) F. Garcia and C. Galvez, Synthesis, 1985, 143; 11 S. Bhagat and A. K. Chakraborti, J. Org. Chem., 2007, 72,
(b) L. Klasinc and N. Trinajstic, Tetrahedron, 1971, 27, 4045. 1263.
3 (a) D. S. Matteson and H. R. Snyder, J. Am. Chem. Soc., 12 T. S. A. Heugebaert, B. I. Roman and C. V. Stevens, Chem.
1957, 79, 3610; (b) W. W. Gale, A. N. Scott and H. R. Snyder,
Soc. Rev., 2012, 41, 5626.
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 2932–2935 | 2935