Radical-Cascade Avenue for 3,4-Fused-Ring-Substituted Thiophenes

Article abstract of DOI:10.1021/acs.orglett.8b01577

A single-step intramolecular radical cascade reaction of diynes and thioacetic acid in the presence of a catalytic amount of azobis(isobutyronitrile) as a radical initiator has been developed to synthesize thiophenes. This method allows easy and effective construction of a thiophene scaffold having 3,4-fused-ring substitution and unsubstituted 2,5-positions for further functionalization and polymerization. Using this method, derivatives of cyclopenta[c]thiophene, 3,4-ethylenedioxythiophene, and thiophene-containing spirocyclic compound have been synthesized.

Full text of DOI:10.1021/acs.orglett.8b01577

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Radical-Cascade Avenue for 3,4-Fused-Ring-Substituted Thiophenes
Abhijeet R. Agrawal,† Neha Rani Kumar,† Sashi Debnath,‡ Sarasija Das, Chandan Kumar,
and Sanjio S. Zade*
Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Kolkata, Mohanpur 741246, Nadia,
West Bengal, India
S
* Supporting Information
ABSTRACT: A single-step intramolecular radical cascade reaction of diynes
and thioacetic acid in the presence of a catalytic amount of azobis-
(isobutyronitrile) as a radical initiator has been developed to synthesize
thiophenes. This method allows easy and effective construction of a thiophene
scaffold having 3,4-fused-ring substitution and unsubstituted 2,5-positions for
further functionalization and polymerization. Using this method, derivatives of
cyclopenta[c]thiophene, 3,4-ethylenedioxythiophene, and thiophene-containing
spirocyclic compound have been synthesized.
hiophene-based conjugated systems have shown remark-
able properties which allow them to be used as active
5-membered ring at the 3,4-positions of thiophene leaving the
2,5-positions vacant for further functionalization is a tedious
job involving multistep reactions.7
T
materials for organic electronic devices.1 Thiophene is also a
prevalent structural unit of biologically active compounds.2,3
Unsubstituted polythiophene (A, Figure 1) has excellent
Indeed, MacDowell et al.8 reported the first synthesis of
CPT, involving seven steps (Scheme 1a). Otsubo et al.9
reported the synthesis of CPT in three steps starting from 2,5-
dibromo-3,4-bis(bromomethyl)thiophene (Scheme 1b). Tilley
et al.10 reported the synthesis of CPT using the Fagan−Nugent
reaction,11 which is a three-step synthesis (Scheme 1c)
involving an expensive zirconium catalyst.12 Recently,
Figure 1. Polythiophene, poly(3-hexylthiophene), and poly(3,4-
dialkylthiophene)s.
Scheme 1. Different Approaches To Synthesize
Cyclopenta[c]thiophene
environmental stability but lacks the necessary solution
processability.4 Solution-processable regioregular poly(3-hex-
ylthiophene) (B, Figure 1) is an example of one of the most
studied polythiophenes. However, synthesis of regioregular
poly(3-hexylthiophene) requires specific synthetic strategies
due to unsymmetrical substitution on thiophene ring.
Symmetric substitution at the 3- and 4-positions of thiophene
solves the problem of regiochemistry, but polythiophenes
having 3,4-dialkyl/aryl substituents (such as C, Figure 1) or
3,4-substitution in the form of fused six-membered or higher
rings deviate from planarity due to steric repulsion. On the
other hand, polycyclopenta[c]thiophene (PCPT) (D, Figure
1)5 is planar and devoid of the problem of regiochemistry.
Indeed, we and others6 have shown that incorporation of
3,4-fused five-membered ring on thiophene endows excellent
planarity to the resulting conjugated polymer (D, Figure 1).
This makes cyclopenta[c]thiophene a suitable precursor for
conjugated systems in the field of organic electronics.
Significant efforts have been made by various research groups
for synthesizing CPT derivatives. However, incorporation of a
Received: May 18, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01577
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Yamamoto and co-workers13 have demonstrated the synthesis
of 3,4-fused-ring-substituted thiophenes using expensive
Ruthenium catalyst and special sulfur donor (Scheme 1d).
Both of the above methods10,13 afford 2,5-substituted (aryl/
alkyl or silyl) thiophenes.
Scheme 2. Substrate Scope for AIBN and Thioacetic Acid
Mediated CPT Synthesis
We reported the first synthesis of a selenium analogue of
CPT, cyclopenta[c]selenophene,14 and extended the synthetic
strategy to synthesize the selenophene analogue of 3,4-
ethylenedioxythiophene (EDOT), 3,4-ethylenedioxyseleno-
phene (EDOS),15 in two steps from the diyne precursors
with an overall yield of 20−40%. The possibility of introducing
a solubilizing group on CPT monomer inspired us to
synthesize several CPT-based polymers to study their
applications in organic electronic devices. Herein, we present
a simple yet effective single-step radical cascade strategy for the
synthesis of various CPT derivatives using 1,5-hexadiyne
precursors and thioacetic acid as sulfur source and azobis-
(isobutyronitrile) (AIBN) as radical initiator in common
hydrocarbon solvents (toluene). This method also meets the
important principle of green chemistry by avoiding the
unnecessary derivatization.16 Most of the previous synthetic
routes required end groups on the diyne precursors which
result in 2,5-substituents in the resulting thiophene derivatives.
The feasibility of the synthetic approach was first established
with model substrate 1a. To optimize the reaction conditions,
different sources of thiyl radical17 and radical initiators were
screened. Thioacetic acid and tert-butyl thiol were chosen as
sources of thiyl radicals, which contain acetyl and tert-butyl
radical stabilizing groups, respectively. To this end, conven-
tional radical initiators such as AIBN, 2,2,6,6-tetramethylpiper-
idin-1-yl)oxyl (TEMPO), and benzoyl peroxide were used.
Based on the thiyl radical sources and radical initiators,
different reaction conditions were applied to reach the
optimized conditions (Table S1). Both thioacetic acid and
tert-butyl thiol acted as potential sources of sulfur for the
radical-mediated synthesis of thiophene. However, it turned
out that 1.5 equiv of thioacetic acid gave the highest yield.
AIBN was found to be slightly more efficient in giving the
desired product than the other two radical initiators.
Therefore, AIBN and thioacetic acid were chosen to further
evaluate the substrate scope. The yield of the reaction was also
investigated in terms of catalyst loading from 5% to 20% and
the highest yield was obtained when 5% of catalyst loading was
employed. The yields remained nearly constant with further
increasing amount of catalyst.
*
Yield of the reactions on a 10 mmol scale.
Scheme 3. (a) AIBN- and CH3COSH-Mediated Synthesis of
EDOT; (b) Incorporation of Heteroatom in Cyclopentane
Ring
aromatic substituents were introduced. Thus, benzyloxy-
substituted CPT 2h and the spirocyclic fluorene derivative 2i
were synthesized in 58% and 60% yields, respectively.
Spirocyclic compound 2i was unambiguously confirmed by
single-crystal X-ray analysis (Figure 2). A similar spirocyclic
To explore the scope of the method, a variety of diyne
substrates (1a−m) were tested using AIBN and thioacetic acid
in toluene at 80 °C as shown in Scheme 2 and 3. Diynes 1a−
k18 easily underwent the desired cascade radical cyclization
reaction with the thiyl radical to give 3,4-ring-substituted
thiophene derivatives. Initially, 4,4-dialkoxymethyl-substituted
1,5-hexadiynes were screened. The reactions with 1a and 1b
afforded the expected cyclopenta[c]thiophene derivatives 2a
and 2b in 51% and 48% yields, respectively.
Figure 2. Crystal structure of spirocyclic compound 2i.
Diester derivative 2c and diacyl derivative 2d were
synthesized from the diyne precursor 1c and 1d in 44% and
50% yields, respectively. Further, the reactions with unsym-
metrical 4,4-disubstituted 1,5-hexadiynes 1e−g were attemp-
ted. These unsymmetrical substituents include acyl-ester (2e),
cyano-ester (2f) and H-cyano (2g)19 groups. The reactions of
the diynes 2e−g afforded the expected unsymmetrical CPT
derivatives in 60%, 10%, and 45% yields, respectively. It was
observed that the reactions were significantly clean when
compound with 2,5-diphenyl substituents was reported by
Yamamoto et al.13 However, an unsubstituted analogue is more
desirable as it allows further derivatization through the 2,5-
positions.
This method was effectively extended to synthesize six-
membered fused-ring thiophene derivatives. Thus, we have
obtained EDOT (2j) starting from the diyne precursor 1j in
48% yield (Scheme 3a). The most common and industrially
applied route for the synthesis of EDOT is the Hinsberg20
B
DOI: 10.1021/acs.orglett.8b01577
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
reaction which include the reaction of thiodiacetic acid diethyl
ester and glyoxal followed by the reaction with 1,2-dihalo-
when we performed the reaction with phenyl capped diyne 3,
no product formation was observed (Scheme 4b). It indicates
the importance of terminal diyne for the formation of
thiophene through cascade radical reaction. The intra-
molecular nature of this reaction was again confirmed when
the thiyl radical was reacted with 2 equiv of isolated diynes.
When phenyl acetylene 5 (2 equiv) was subjected to similar
reaction conditions, the in situ formed thiyl radical reacted
with phenyl acetylene to give only compound 6 in quantitative
yield (Scheme 4c).
As an example of functionalization at 2,5-positions,
dibromination reaction of compounds 2f, 2g, and 2j was
carried out by treatment with NBS in chloroform in the
presence of a few drops of acetic acid. The corresponding
dibromo derivatives were obtained in very good yields
(Scheme 5). These dibromo derivatives can be further used
for standard coupling reactions and polymerization.
ethanes. Bauerle et al. employed Mitsunobu reaction of 3,4-
̈
dihydroxythiophene derivatives with diols.21 Our group also
reported the synthesis of EDOT and EDOS15 by using the
Fagan−Nugent reaction. However, the present method is more
operationally simple and effective than our previous strategy.
The scope of the method was also established by carrying out a
gram-scale (10 mmol) synthesis of 2d, 2e, and 2i. On this
scale, compounds 2d, 2e, and 2i were obtained in 46%, 49%,
and 49% yields, respectively. However, the reaction required
prolonged heating for completion (up to 18 h).
To extend the scope of the method, we investigated the
reactions for the incorporation of heteroatoms in the
cyclopentane ring (Scheme 3b). Thus, thieno[3,4-c]furan
(2k) was obtained from the diyne precursor 1k in 43% yield.
However, all attempts to obtain compound 2l and 2m from
alkyl- and benzyl-substituted nitrogen containing diynes 1l and
1m, respectively, were unsuccessful.22
A plausible reaction mechanism for the formation of the
thiophene ring may be envisioned as radical cascade initiated
by the thiyl radical at the terminal position of diyne (Scheme
4a). Regioselective addition of the thiyl radical to one of the
Scheme 5. Bromination of CPT Derivatives, and EDOT
Scheme 4. (a) Plausible Mechanism of Radical-Mediated
Synthesis of CPT Using CH3COSH and AIBN, (b) Attempt
To Synthesize Phenyl-Capped CPT, (c) Reaction of Phenyl
Acetylene with Thiyl Radical
Replacement of sulfur by the more polarizable selenium
offers an interesting route to create new conjugated systems.26
On the basis of this synthetic strategy, synthesis of the
cyclopenta[c]selenophene derivative was attempted using
compound 1a, AIBN, and in situ generated benzoyl selenol
and tert-butyl selenol, respectively, as the source of selenyl
radical (Scheme S1). However, all reactions failed to afford the
desired products. Instead, unreacted diyne precursor 1a and
the corresponding diselenides were obtained (Scheme S1).
In summary, a synthetic approach for the synthesis of 3,4-
fused-ring-substituted thiophene derivatives with unsubstituted
2,5-positions was developed through the reaction of thiyl
radical with terminal intramolecular diynes. Cyclopenta[c]-
thiophene (CPT) derivatives, 3,4-ethylenedioxythiophene
(EDOT), and thieno[3,4-c]furan were successfully synthesized
by using this approach. This method offers an operationally
easier and simpler process to obtain 3,4-fused-ring-substituted
thiophene derivatives with unsubstituted 2,5-positions. By
changing a linker between terminal alkynes, this process can be
extended to synthesize many 3,4-fused-ring-substituted thio-
phenes.
ASSOCIATED CONTENT
* Supporting Information
■
S
triple bonds of 1,6-hexadiynes produces an E/Z mixture of
vinyl radical intermediates in equilibrium. Only the E-vinyl
radical intermediate can lead to the formation of the desired
bicyclic product (CPT). The second cyclization proceeds
through the liberation of the acyl radical via intramolecular
homolytic substitution (SH2) at sulfur by the s-cis butadienyl
radical (Scheme 4a).22,23 After the first cyclization, Z-vinyl
radical intermediates might be participating further radical
reactions to form oligo- and polymeric products. Therefore,
the attempts to isolate the other side-products were
unsuccessful except in the reaction of fluorene-substituted
diyne. In this reaction, along with 2i, 2i-bp was obtained in
∼20% yield. It confirms the formation of thiyl radical
intermediate and its attack on the terminal alkyne.24,25 Indeed,
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01577.
Experimental details, characterization data, NMR spectra
and crystal structure information (PDF)
Accession Codes
CCDC 1840677 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
C
DOI: 10.1021/acs.orglett.8b01577
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Letter
1
determined from H NMR) remained constant after 8 h. Moreover,
the product cannot be separated from the reactants despite repeated
column chromatography. After dibromination, product was easily
separable from the reactants. Therefore, the product was used for
bromination reaction without further purification and isolation.
(20) Dallacker, F.; Mues, V. Chem. Ber. 1975, 108, 569−575.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sanjiozade@iiserkol.ac.in.
ORCID
Sanjio S. Zade: 0000-0001-8902-257X
Present Address
‡Department of Radiology & Advanced Imaging Research
Center, The University of Texas Southwestern Medical Center,
Clements Imaging Building, 2201 Inwood Road, Dallas, TX
75390.
̈
(21) Caras-Quintero, D.; Bauerle, P. Chem. Commun. 2002, 2690−
2691.
(22) Padwa, A.; Nimmesgern, H.; Wong, G. S. K. J. Org. Chem.
1985, 50, 5620−5627.
(23) (a) Chatgilialoglu, C.; Crich, D.; Komatsu, M.; Ryu, I. Chem.
Rev. 1999, 99, 1991−2069. (b) Tada, M.; Nakagiri, H. Tetrahedron
Lett. 1992, 33, 6657−6660. (c) Beckwith, A. L. J.; Duggan, S. A. M. J.
Chem. Soc., Perkin Trans. 2 1994, 2, 1509−1518. (d) Crich, D.; Yao,
Q. J. Org. Chem. 1996, 61, 3566−3570. (e) Crich, D.; Hao, X. J. Org.
Chem. 1997, 62, 5982−5988.
Author Contributions
†A.R.A. and N.R.K. contributed equally.
Notes
(24) Wille, U. Chem. Rev. 2013, 113, 813−853.
(25) Denes, F.; Pichowicz, M.; Povie, G.; Renaud, P. Chem. Rev.
2014, 114, 2587−2693.
́
̀
The authors declare no competing financial interest.
(26) (a) Aqad, E.; Lakshmikantham, M. V.; Cava, M. P. Org. Lett.
2001, 3, 4283−4285. (b) Heeney, M.; Zhang, W.; Crouch, D. J.;
Chabinyc, M. L.; Gordeyev, S.; Hamilton, R.; Higgins, S. J.;
McCulloch, I.; Skabara, P. J.; Sparrowe, D.; Tierney, S. Chem.
Commun. 2007, 5061−5063. (c) Patra, A.; Wijsboom, Y. H.; Zade, S.
S.; Li, M.; Sheynin, Y.; Leitus, G.; Bendikov, M. J. Am. Chem. Soc.
2008, 130, 6734−6736.
ACKNOWLEDGMENTS
■
We acknowledge SERB, India, for financial support (project
no. EMR/2015/000241). A.R.A., S.D., and C.K. thank IISER
Kolkata for fellowships. N.R.K. thanks DST for an INSPIRE
fellowship. We thank Dr. Prakash P. Wadgaonkar (CSIR-NCL,
Pune) for HRMS data.
REFERENCES
■
(1) Handbook of Thiophene-Based Materials: Applications in Organic
Electronics and Photonics; Peripichka, I. F., Peripichka, D. F., Eds.;
John Wiley & Sons: New York, 2009; Vols. 1 and 2.
(2) Barbarella, G.; Melucci, M.; Sotgiu, G. Adv. Mater. 2005, 17,
1581−1593.
(3) Wu, C.; Decker, E. R.; Blok, N.; Bui, H.; You, T. J.; Wang, J.;
Bourgoyne, A. R.; Knowles, V.; Berens, K. L.; Holland, G. W.; Brock,
T. A.; Dinon, R. A. F. J. Med. Chem. 2004, 47, 1969−1986.
(4) (a) Frommer, J. E. Acc. Chem. Res. 1986, 19, 2−9. (b) Roncali, J.
Chem. Rev. 1992, 92, 711−738.
(5) Zade, S. S.; Zamoshchik, N.; Bendikov, M. Chem. - Eur. J. 2009,
15, 8613−8624.
(6) Roncali, J.; Garnier, F.; Garreau, R.; Lemaire, M. J. Chem. Soc.,
Chem. Commun. 1987, 1500−1502.
(7) Tourillon, G.; Garnier, F. J. Electroanal. Chem. Interfacial
Electrochem. 1984, 161, 51−58.
(8) MacDowell, D. W. H.; Patrick, T. B.; Frame, B. K.; Ellison, D. L.
J. Org. Chem. 1967, 32, 1226−1229.
(9) Izumi, T.; Kobashi, S.; Takimiya, K.; Aso, Y.; Otsubo, T. J. Am.
Chem. Soc. 2003, 125, 5286−5287.
(10) Jiang, B.; Tilley, T. D. J. Am. Chem. Soc. 1999, 121, 9744−9745.
(11) Fagan, P. J.; Nugent, W. A. J. Am. Chem. Soc. 1988, 110, 2310−
2312.
(12) Yan, X.; Xi, C. Acc. Chem. Res. 2015, 48, 935−946.
(13) Matsui, K.; Shibuya, M.; Yamamoto, Y. Angew. Chem., Int. Ed.
2016, 55, 15397−15400.
(14) Das, S.; Zade, S. S. Chem. Commun. 2010, 46, 1168−1170.
(15) Das, S.; Dutta, P. K.; Panda, S.; Zade, S. S. J. Org. Chem. 2010,
75, 4868−4871.
(16) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and
Practice; Oxford University Press: New York, 1998.
(17) Harrowven, D. C.; Hannam, J. C.; Lucas, M. C.; Newman, N.
A.; Howes, P. D. Tetrahedron Lett. 2000, 41, 9345−9349.
(18) (a) Shi, Y.; Gevorgyan, V. Org. Lett. 2013, 15, 5394−5396.
(b) Madine, J. W.; Wang, X.; Widenhoefer, R. A. Org. Lett. 2001, 3,
385−388. (c) Smithers, R. H. Synthesis 1985, 1985, 556−558.
(d) Korneev, S.; Rosemeyer, H. Helv. Chim. Acta 2013, 96, 201−216.
(e) Richard, V.; Ipouck, M.; Merel, D. S.; Gaillard, S.; Whitby, R. J.;
Witulski, B.; Renaud, J. Chem. Commun. 2014, 50, 593−595.
(19) This reaction did not undergo completion despite prolonged
reaction time and addition of an excess of AIBN. Reaction yield (as
D
DOI: 10.1021/acs.orglett.8b01577
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