Construction of Heteroacenes with Fused Thiophene and Pyrrole Rings via the Fischer Indolization Reaction

Article abstract of DOI:10.1021/acs.orglett.6b00081

A convenient approach to ladder-type 6H-benzo[4′,5′]thieno[2′,3′:4,5]thieno[3,2-b]indoles bearing various substituents in both terminal benzene rings has been developed. The protocol suggested for preparing these N,S-heteroacenes is based on using easily

Full text of DOI:10.1021/acs.orglett.6b00081

Letter
pubs.acs.org/OrgLett
Construction of Heteroacenes with Fused Thiophene and Pyrrole
Rings via the Fischer Indolization Reaction
Roman A. Irgashev,*,†,‡ Arseny A. Karmatsky,†,‡ Gennady L. Rusinov,†,‡ and Valery N. Charushin†,‡
†Postovsky Institute of Organic Synthesis, Ural Division of the Russian Academy of Sciences, Ekaterinburg 620990, Russia
‡Ural Federal University named after the First President of Russia, B.N. Yeltsin, Ekaterinburg 620002, Russia
S
* Supporting Information
ABSTRACT: A convenient approach to ladder-type 6H-
benzo[4′,5′]thieno[2′,3′:4,5]thieno[3,2-b]indoles bearing var-
ious substituents in both terminal benzene rings has been
developed. The protocol suggested for preparing these N,S-
heteroacenes is based on using easily available reagents, such as
cinnamic acids and arylhydrazines, which can be involved in
the Fischer indole synthesis, as the key step. A similar
condensed system of 12H-benzo[4″,5″]thieno[2″,3″:4′,5′]-
thieno[2′,3′:4,5]thieno[3,2-b]indole, bearing six rings, has
also been obtained.
significant and growing number of publications dealing
Awith various classes of π-conjugated polycyclic molecules,
including acenes and their heteroanalogues (heteroacenes),
have emerged during the past decade. Successful applications of
these compounds have been presented, specifically as active
materials for high-performance organic electronic devices, such
as organic field-effect transistors (OFETs),1 organic light-
emitting diodes (OLEDs),2 and different kinds of organic
photovoltaics (OPVs).3 Pentacene and some higher acenes,
such as hexa- or heptacenes, are excellent organic semi-
conductors, showing outstanding characteristics of charge
carrier mobility.4 However, these compounds possess low
stability under ambient conditions due to high-lying HOMO
energy levels, which strongly restrict their practical applica-
tions.5 Compared with acenes, electron-rich heteroacenes,
bearing fused thiophene and/or pyrrole rings, instead of the
benzene units in the parent aromatic hydrocarbons, not only
exhibit better electronic characteristics but are also more
resistant to degradation. Generally, heteroacenes have a higher
structural versatility because of a variety of combinations of
aromatic and heteroaromatic units that provide desired tuning
for target structures. Many heteroacene derivatives based on
thiophene and/or pyrrole units have recently been suggested as
promising materials for electronic and optoelectronic devices.6
In this context, there is a strong demand for new heteroacenes;
therefore, the development of convenient synthetic approaches
to their frameworks is an important topic for both organic
chemistry and material science. From an organic synthesis point
of view, a good strategy should provide easy access to a
diversity of heteroacene derivatives for further design of more
complicated molecules to develop materials with improved
properties.
type structure, namely 6H-benzo[4′,5′]thieno[2′,3′:4,5]thieno-
[3,2-b]indoles (BTTIs). Moreover, the suggested approach
enables one to vary substituents in both terminal benzene rings
of the BTTI scaffold. It is noteworthy that three isomeric
heteroacenes 1−3 with different dispositions of two thiophene
and one pyrrole rings, located between two terminal benzene
fragments, have been described previously in the literature
(Figure 1).7
Figure 1. Structures of BTTI and the known isomers.
The key step in the synthesis of heteroacenes 1−3 is the
formation of central pyrrole ring using the Cadogan reductive
cyclization7a or the Buchwald−Hartwig amination,7b although
variation of substituents merely at the nitrogen atom in these
heterocycles has also been demonstrated.
Several ring-closure reactions appear suitable for construction
of the BTTI core, and they should be discussed in order to
select the most acceptable route. In fact, the BTTI structure can
be formed using the Cadogan cyclization8a of 2-nitrophenyl,
containing benzo[b]thieno[2,3-d]thiophenes A (route 2,
Scheme 1), triflic acid catalyzed cyclization8b of 2-methyl-
In this paper, we report a robust and convenient way for the
synthesis of new asymmetric N,S-heteroacenes, having a ladder-
Received: January 11, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00081
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Letter
Scheme 1. Synthetic Routes to the Formation of BTTI
Scaffold
Scheme 2. Synthesis and Structures of Benzo[b]thieno[2,3-
d]thiophenes Derivatives 5 and 6
sulfinylphenyl-containing indoles B (route 3, Scheme 1), or
related cyclization of thieno[3,2-b]indoles C (route 4, Scheme
1). A reasonable approach to precursors A−C is provided by
the Suzuki−Miyaura or the Stille cross-coupling reactions
between properly selected (hetero)aryl halides and organo-
boron or organotin (hetero)arenes, respectively (for instance,
the formation of precursor A using the Stille cross-coupling of
8c
stannane A1 with 1-bromo-2-nitrobenzene, Scheme 1).
a
TFA/MsOH (v/v, 1:1) was used instead of sulfuric acid.
However, synthetic routes to the BTTI scaffold discussed
above have some disadvantages; namely, they require expensive
and nonenvironmentally friendly transition metals, highly toxic
phosphine ligands and organotin compounds (for the Stille
reaction), as well as some pyrophoric reagents (e.g., n-BuLi) for
prefunctionalization of (het)aromatic fragments. All these
features eventually lead to a low availability of the target
compounds. The synthesis of BTTI structure can also be
realized via the Fischer reaction,9 which avoids the mentioned
above difficulties, and thereby the Fischer indolization process
has been selected as the key step for the synthesis of the BTTI
core (route 1, Scheme 1). It should be mentioned that, for
instance, the double-Fischer cyclization of bis-arylhydrazones of
cyclohexa-1,4-dione provides an easy access to 5,11-
dihydroindolo[3,2-b]carbazoles, which constitute an important
class of N-heteroacenes with a wide range of applications in
organic electronic devices.10
According to the selected synthetic procedure, benzo[b]-
thieno[2,3-d]thiophen-3(2H)-ones proved to be major pre-
cursors of BTTI compounds, and their preparation became the
starting point for its implementation. The closest analogues of
these tricyclic ketones, such as thieno[3,2-b]thiophen-3(2H)-
ones, have been synthesized previously by cyclization of 2-
(thien-3-ylthio)acetic acids in polyphosphoric acid in low
yields.11 At the same time, compounds with the thiophen-
3(2H)-one moiety were synthesized in good yields by facile
decarboxylation of the corresponding 3-hydroxythiophene-2-
carboxylic acids.12 In this connection, tricyclic 3-hydroxyesters
5a−f were prepared by the Fiesselmann-like reaction13 from
ethyl 3-chlorobenzo[b]thiophene-2-carboxylates 4a−f and ethyl
mercaptoacetate in the presence of an excess of potassium tert-
butoxide (Scheme 2). The starting materials 4a−f bearing the
benzo[b]thiophene scaffold have been obtained by treatment of
the corresponding cinnamic acids with thionyl chloride,
according to the reported procedure.14
to realize its hydrolysis with a mixture of concentrated
hydrochloric and glacial acetic acids (v/v, 1:1) under similar
conditions, have failed, and the starting material 5a was
recovered in both cases. Successful hydrolysis of the ester 5a
followed by decarboxylation of the formed acid has been
performed in a solution of 90% sulfuric acid on mild heating of
the reaction mixture up to 80 °C, thus affording tricyclic ketone
6a in 75% yield. It is especially important to maintain the
temperature of the current process below 80 °C because the
yield of the product 6a becomes lower in the case of even a
short-term overheating of the reaction mixture. Other ketones
6b−f have been synthesized from the corresponding esters 5b−
f in the same manner.
However, conversion of raw materials 5d−f in sulfuric acid
was very slow, and it caused significant degradation of the
reaction products 6d−f due to a prolonged contact with a
strong acid under heating. This problem was solved using a
mixture of trifluoroacetic (TFA) and methanesulfonic (MsOH)
acids (v/v, 1:1), instead of sulfuric acid, for hydrolysis of esters
5d−f resulting in ketones 6d−f in good yields (Scheme 2).
It has been found that ketones 6a−f react with phenyl-
hydrazine hydrochloride 7a (1.2 equiv) in the presence of
anhydrous sodium acetate (2 equiv) in a glacial acetic acid
when heated under reflux for 1 h, and the initially formed
hydrazones of 6 are easily indolized into BTTIs 8a−f under
these conditions without isolation of intermediates (field A,
Scheme 3). The synthesis of compounds 8g−k with
substituents in the fused benzene ring of the indole part of
the molecules has been performed easily by treatment of ketone
6a with hydrochloric salts of the corresponding arylhydrazines
7b−f under the same reaction conditions (field B, Scheme 3).
Therefore, two sets of the target BTTI heteroacenes 8
containing various substituents in both benzene rings have
been prepared successfully using the Fischer reaction as the key
step of these transformations.
All attempts to cause saponification of ester 5a in a refluxing
solution of potassium hydroxide in ethanol for 12 h, as well as
B
DOI: 10.1021/acs.orglett.6b00081
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Scheme 3. Synthesis and Structures of BTTI Derivatives 8 Prepared by the Fischer Indolization Reaction
N-Substituted derivatives 9a−c were prepared by alkylation
of the starting compound 8a as an example of modification of
the BTTI core. This synthesis was carried out in DMSO
solution at room temperature in the presence of potassium tert-
butoxide as a base (Scheme 4). Evidence for the structure of
afforded the corresponding triflate 10 in a quantitative yield.
The latter readily reacts with ethyl mercaptoacetate under
conditions similar to those used for preparation of compound
5a to obtain tetracyclic 3-hydroxyester 11. Hydrolysis of the
ester 11, followed by decarboxylation in a mixture of
trifluoroacetic (TFA) and methanesulfonic (MsOH) acids,
has produced the key precursor 12, which has been
transformed consequently into the target six-ring heterocyclic
system 13 (BTTTI) according to the Fischer reaction (Scheme
5).
Scheme 4. Synthesis of N-Substituted BTTIs 9a−c
Scheme 5. Synthesis of Six-Ring Heteroacene 13
BTTI compounds 8 has been obtained unequivocally by X-ray
crystallography analysis performed for the single-crystal sample
of 6-benzyl-substituted derivative 9a (Figure 2; see also the SI),
1
thus supporting the H and 13C NMR spectroscopic data.
The suggested approach to the formation of BTTI molecules
has also been applied successfully for the synthesis of
heteroacenes bearing six rings with one extra thiophene block
in its ladder-type BTTI framework. Thus, treatment of 3-
hydroxyester 5a with triflic anhydride (Tf2O) in the presence of
triethylamine and 4-(dimethylamino)pyridine (DMAP) has
In summary, we have described a convenient approach to
construct derivatives of an unknown heterocyclic system,
namely 6H-benzo[4′,5′]thieno[2′,3′:4,5]thieno[3,2-b]indoles,
bearing substituents in both terminal benzene rings, on the
basis of the Fischer indole synthesis, as the key step. The three-
step synthesis of these N,S-heteroacenes has been realized,
starting from ethyl 3-chlorobenzo[b]thiophene-2-carboxylates,
which have been prepared from easily accessible cinnamic acids.
In addition, the synthesis of a six-ring heterocyclic system of
12H-benzo[4″,5″]thieno[2″,3″:4′,5′]thieno[2′,3′:4,5]thieno-
[3,2-b]indole has been performed using this strategy. The
further design and synthesis of new heteroacene structures
using this reaction sequence, as well as the elucidation of optic
Figure 2. X-ray single crystal structure of derivative 9a. Thermal
ellipsoids of 50% probability are presented.
C
DOI: 10.1021/acs.orglett.6b00081
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Letter
Bettinger, H. F. Angew. Chem., Int. Ed. 2013, 52, 9818−9820. (c) Zade,
S. S.; Bendikov, M. J. Phys. Org. Chem. 2012, 25, 452−461. (d) Zade,
S. S.; Bendikov, M. Angew. Chem., Int. Ed. 2010, 49, 4012−4015.
(6) (a) Anthony, J. E. Chem. Rev. 2006, 106, 5028−5048. (b) Izawa,
T.; Takimiya, K. J. Am. Chem. Soc. 2007, 129, 2224−2225.
(c) Miyazaki, E.; Takimiya, K. Chem. Mater. 2009, 21, 903−912.
(d) Gao, P.; Cho, D.; Yang, X. Y.; Enkelmann, V.; Baumgarten, M.;
and electronic properties of BTTI and BTTTI compounds, are
currently in progress.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00081.
Mullen, K. Chem. - Eur. J. 2010, 16, 5119−5128. (e) Simokaitiene, J.;
̈
Stanislovaityte, E.; Grazulevicius, J. V.; Jankauskas, V.; Gu, R.; Dehaen,
W.; Hung, Y. C.; Hsu, C. P. J. Org. Chem. 2012, 77, 4924−4931.
(f) Mori, T.; Nishimura, T.; Yamamoto, T.; Doi, I.; Miyazaki, E.;
Osaka, I.; Takimiya, K. J. Am. Chem. Soc. 2013, 135, 13900−13913.
(g) Park, J.-I.; Chung, J. W.; Kim, J.-Y.; Lee, J.; Jung, J. Y.; Koo, B.; Lee,
B.-L.; Lee, S. W.; Jin, Y. W.; Lee, S. Y. J. Am. Chem. Soc. 2015, 137,
Experimental procedures, UV−vis absorption spectra of
compounds 8a−c,f,h,i,k and 13, characterization data for
1
all new compounds, and H, 13C, and 19F NMR spectra
(PDF)
́
12175−12178. (h) Niebel, C.; Kim, Y.; Ruzie, C.; Karpinska, J.;
Crystallographic data for 9a (CIF)
Chattopadhyay, B.; Schweicher, G.; Richard, A.; Lemaur, V.; Olivier,
Y.; Cornil, J.; Kennedy, A. R.; Diao, Y.; Lee, W. Y.; Mannsfeld, S.; Bao,
Z.; Geerts, Y. H. J. Mater. Chem. C 2015, 3, 674−685. (i) Jung, I. H.;
Kim, J.-H.; Nam, S. Y.; Lee, C.; Hwang, D.-H.; Yoon, S. C.
Macromolecules 2015, 48, 5213−5221.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: irgashev@ios.uran.ru.
Notes
(7) (a) Qi, T.; Guo, Y.; Liu, Y.; Xi, H.; Zhang, H.; Gao, X.; Liu, Y.;
Lu, K.; Du, C.; Yu, G.; Zhu, D. Chem. Commun. 2008, 6227−6229.
(b) Balaji, G.; Valiyaveettil, S. Org. Lett. 2009, 11, 3358−3361.
(8) (a) Cadogan, J. I. G.; Mackie, R. K. Chem. Soc. Rev. 1974, 3, 87−
137. (b) Huang, J.; Luo, H.; Wang, L.; Guo, Y.; Zhang, W.; Chen, H.;
Zhu, M.; Liu, Y.; Yu, G. Org. Lett. 2012, 14, 3300−3303. (c) Mallet,
C.; Savitha, G.; Allain, M.; Kozmik, V.; Svoboda, J.; Frere, P.; Roncali,
J. J. Org. Chem. 2012, 77, 2041−2046.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Russian Foundation for Basic
Research (Research Project No. 15-03-00924_A, 16-33-00157-
mol_a) and the Scientific Council of the President of the
Russian Federation (Grant No. MK-4509.2016.3).
(9) Robinson, B. Chem. Rev. 1963, 63, 373−401.
(10) (a) Tholander, J.; Bergman, J. Tetrahedron 1999, 55, 12577−
12594. (b) Yudina, L. N.; Bergman, J. Tetrahedron 2003, 59, 1265−
1275.
REFERENCES
■
(11) Archer, W. J.; Taylor, R. J. Chem. Soc., Perkin Trans. 2 1982,
295−299.
(12) (a) Carpenter, W.; Snyder, H. R. J. Am. Chem. Soc. 1960, 82,
2592−2597. (b) Dinescu, L.; Maly, K. E.; Lemieux, R. P. J. Mater.
Chem. 1999, 9, 1679−1686.
(13) (a) Fiesselmann, H.; Schipprak, P. Chem. Ber. 1954, 87, 835−
841. (b) Fiesselmann, H.; Schipprak, P.; Zeitler, L. Chem. Ber. 1954,
87, 841−848. (c) Fiesselmann, H.; Pfeiffer, G. Chem. Ber. 1954, 87,
848−856. (d) Fiesselmann, H.; Thoma, F. Chem. Ber. 1956, 89, 1907−
1912. (e) Fiesselmann, H.; Schipprak, P. Chem. Ber. 1956, 89, 1897−
1902.
(14) (a) Higa, T.; Krubsack, A. J. J. Org. Chem. 1975, 40, 3037−3045.
(b) Ried, W.; Oremek, G.; Ocakcioglu, B. Liebigs Ann. Chem. 1980,
1980, 1424−1427.
(1) (a) Wu, W.; Liu, Y.; Zhu, D. Chem. Soc. Rev. 2010, 39, 1489−
1502. (b) Zschieschang, U.; Ante, F.; Kalblein, D.; Yamamoto, T.;
̈
Takimiya, K.; Kuwabara, H.; Ikeda, M.; Sekitani, T.; Someya, T.;
Nimoth, J. B.; Klauk, H. Org. Electron. 2011, 12, 1370−1375.
(c) Watanabe, M.; Chen, K. Y.; Chang, Y. J.; Chow, T. J. Acc.
Chem. Res. 2013, 46, 1606−1615. (d) Wang, M.; Li, J.; Zhao, G. Y.;
Wu, Q. H.; Huang, Y. G.; Hu, W. P.; Gao, X.; Li, H.; Zhu, D. Adv.
Mater. 2013, 25, 2229−2233. (e) Takimiya, K.; Osaka, I.; Nakano, M.
Chem. Mater. 2014, 26, 587−593.
(2) (a) Organic Light Emitting Devices: Synthesis, Properties and
Applications; Mullen, K., Scherf, U., Eds.; Wiley-VCH: Weinheim,
̈
2006. (b) Lo, S.-C.; Burn, P. L. Chem. Rev. 2007, 107, 1097−1116.
(c) Zhu, M.; Yang, C. Chem. Soc. Rev. 2013, 42, 4963−4976. (d) Liu,
Z. Y.; Xiao, J. C.; Fu, Q.; Feng, H. R.; Zhang, X. M.; Ren, T. J.; Wang,
S.; Ma, D.; Wang, X.; Chen, H. ACS Appl. Mater. Interfaces 2013, 5,
11136−11141.
(3) (a) Lin, Y. Z.; Li, Y. F.; Zhan, X. W. Chem. Soc. Rev. 2012, 41,
4245−4272. (b) Organic Photovoltaics: Materials, Device Physics, and
Manufacturing Technologies, 2nd ed.; Brabec, C., Scherf, U., Dyakonov,
V., Eds.; Wiley-VCH: Mannheim, 2014. (c) Im, J.-H.; Jang, I.-H.;
Pellet, N.; Gratzel, M.; Park, N.-G. Nat. Nanotechnol. 2014, 9, 927−
̈
932. (d) Kazim, S.; Nazeeruddin, M. K.; Gratzel, M.; Ahmad, S. Angew.
̈
Chem., Int. Ed. 2014, 53, 2812−2824. (e) Mazzio, K. A.; Luscombe, C.
̌
K. Chem. Soc. Rev. 2015, 44, 78−90. (f) Steck, C.; Franckevicius, M.;
Zakeeruddin, S. M.; Mishra, A.; Bauerle, P.; Gratzel, M. J. Mater. Chem.
̈
̈
A 2015, 3, 17738−17746.
(4) (a) Kelley, T. W.; Boardman, L. D.; Dunbar, T. D.; Muyres, D.
V.; Pellerite, M. J.; Smith, T. P. J. Phys. Chem. B 2003, 107, 5877−
5881. (b) Payne, M. M.; Parkin, S. R.; Anthony, J. E. J. Am. Chem. Soc.
2005, 127, 8028−8029. (c) Mondal, R.; Adhikari, R. M.; Shah, B. K.;
Neckers, D. C. Org. Lett. 2007, 9, 2505−2508. (d) Purushothaman, B.;
Parkin, S. R.; Anthony, J. E. Org. Lett. 2010, 12, 2060−2063.
(e) Watanabe, M.; Chang, Y. J.; Liu, S.-W.; Chao, T.-H.; Goto, K.;
Islam, M. M.; Yuan, C.-H.; Tao, Y.-T.; Shinmyozu, T.; Chow, T. J. Nat.
Chem. 2012, 4, 574−578.
(5) (a) Maliakal, A.; Raghavachari, K.; Katz, H.; Chandross, E.;
Siegrist, T. Chem. Mater. 2004, 16, 4980−4986. (b) Einholz, R.;
D
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