Gold superacid-catalyzed preparation of benzo[c]thiophenes

Article abstract of DOI:10.1039/c4cc07989b

A three-step synthesis of benzo[c]thiophenes is presented in which the key transformation is the gold-catalyzed 5-exo-dig migratory cycloisomerization of a diallyl thioacetal. It was shown that a small amount of in situ generated HAuCl₄ from AuCl₃ is the active catalytic species. A mechanism was proposed.

Full text of DOI:10.1039/c4cc07989b

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Gold superacid-catalyzed preparation of
benzo[c]thiophenes†
Cite this: Chem. Commun., 2015,
51, 729
Wouter Debrouwer, Ruben A. J. Seigneur, Thomas S. A. Heugebaert and
Christian V. Stevens*
Received 9th October 2014,
Accepted 14th November 2014
DOI: 10.1039/c4cc07989b
www.rsc.org/chemcomm
A three-step synthesis of benzo[c]thiophenes is presented in which
A number of aptly substituted ortho-ethynyl benzaldehydes 1
the key transformation is the gold-catalyzed 5-exo-dig migratory was purchased or prepared via Sonogashira coupling, accord-
cycloisomerization of a diallyl thioacetal. It was shown that a small ing to literature procedures (see ESI†). The substrate scope was
amount of in situ generated HAuCl4 from AuCl3 is the active further expanded using a heterocyclic core, a thiophene-2-
catalytic species. A mechanism was proposed.
carbaldehyde, and an internal alkyne instead of terminal ones.
These substrates were converted into the corresponding diallyl
Benzo[c]thiophenes or isothianaphthenes are of particular interest thioacetals 2 with freshly distilled allyl mercaptan (Caution, see
to material chemists. Most of their applications rely on their ESI† for correct handling) or crotyl mercaptan (2k). Two litera-
presence in oligomers or polymers, bestowing specific photo- ture protocols were applied, one using boron trifluoride in
chemical and -physical features on these materials.1 They are used acetic acid and one using copper sulfate in dichloromethane
in the generation of organic light-emitting diodes (OLEDs),2 as (Scheme 1).12 Electron rich substrates were more efficiently
colorimetric fluoride anion chemosensors,3 as chromophores for
non-linear optics materials,4 NIR contrast agents for biomedical
applications5 and in transistors.5a However, benzo[c]thiophene
oligomers are mostly applied in organic photovoltaic cells (OPV)
due to their small band gap, as a cheaper alternative to silicon
based solar cells.6 Hitherto, benzothiophene-based OPVs with
efficiencies exceeding 7% have been reported.7 Despite the wide
applicability of benzo[c]thiophenes in material sciences, the scope
of reactions to generate them remains relatively limited. It mostly
relies on thionating agents such as Lawesson’s reagent or P2S5,
which display poor atom economy.1,4,5b,6b,8 In other cases, the
benzene ring is annulated onto a thiophene or the corres-
ponding dihydroisothianaphthene is oxidized to the desired
isothianaphthene.2b–e,6a,d,e,h–k,9
Herein, we present a 3-step approach to widely substituted
benzo[c]thiophenes starting from ortho-halobenzaldehydes, of
which many derivatives are commercially available. Based on
our previous experience in the synthesis of 1-phosphono- and
1-cyanoisoindoles and 5-alkylidene-dihydrothiazoles,10 we
envisioned an Au-catalyzed 5-exo-dig migratory cycloisomeriza-
tion to form the thiophene moiety annulated to a benzene ring.11
SynBioC Research Group, Department of Sustainable Organic Chemistry and
Technology, Faculty of Bioscience Engineering, Ghent University,
Coupure Links 653, B-9000 Ghent, Belgium. E-mail: Chris.Stevens@ugent.be
† Electronic supplementary information (ESI) available: Synthetic procedures,
Scheme 1 Formation of diallyl thioacetals 2. Values between parentheses
refer to the ratio of diallyl thioacetal/benzo[c]thiophene. a Reaction at 0 1C.
characterization data and copies of the NMR-spectra. See DOI: 10.1039/
c4cc07989b
This journal is ©The Royal Society of Chemistry 2015
Chem. Commun., 2015, 51, 729--732 | 729

View Article Online
Communication
ChemComm
converted using the latter protocol (1f–g), whereas the other conventionally or by microwave irradiation (60 min, 165 1C), did
substrates gave satisfactory results using the boron trifluoride- not deliver the desired benzo[c]thiophene (entries 1 and 2). The
mediated transformation. Some 30% formation of the corres- use of iron, copper, ammonium, nickel, palladium and silver salts
ponding benzo[c]thiophene was observed for 1g and 5% for 1i, resulted in no conversion after 3 hours of refluxing in dichloro-
according to 1H-NMR integration. These mixtures were chromato- methane (entries 3–8). Also, the use of some mild and very strong
graphically inseparable, so the crude mixture was used as such in protic acids such as acetic acid, sulfuric acid and tetrafluoroboric
the following step.
acid as catalyst proved to be unsuccessful and resulted in full
Sulfur-containing compounds have a reputation of being recovery of starting material (entries 9–13). Addition of BF3ÁEt2O
difficult substrates for catalytic reactions as they can cause or CuSO4 did not yield any benzo[c]thiophene, precluding them
catalyst poisoning. Nevertheless, gold salts and thiols or thioethers as ring-closure catalysts in the earlier dithioacetalization step
have been shown to be compatible.10c,13 Based on our previous (Scheme 1, 2g and 2i). When moving to the previously optimized
work on 5-alkylidene-dihydrothiazoles, a gold catalyzed 5-exo-dig conditions for the synthesis of 5-alkylidene-dihydrothiazoles, using
migratory cycloisomerization was envisioned, yet a selection of AuCl3 in dichloromethane, full consumption of the starting
other catalytic systems was evaluated to ensure optimal reaction material was observed at room temperature within 15 minutes.
conditions (Table 1). No 6-endo-dig cyclization was encountered for AuBr3 and AuCl performed well too, albeit with a drop in isolated
any of the screened catalysts. Heating diallyl thioacetal 2a, either yield or at a slower rate (entries 16–18).
However, when other monovalent Au catalysts were used we
were surprised that no conversion took place at all. This led us
Table 1 Screening of different catalysts
to believe that small amounts of hydrochloric acid, released
from the catalyst by moisture, played a key role in the conver-
sion. The acidity of HCl can be increased in the presence of
AuCl3, by complexation of the chloride and formation of a
HAuCl4 superacid.14 Indeed, when the substrate was treated
with HAuCl4, full conversion to the end product could be
Entry
Catalyst
—
Temp. (1C)
Time (min)
Yield (%)
observed. However, these conditions were too harsh and the
end product showed appreciable degradation, resulting in an
isolated yield of 48%. Upon addition of 10 mol% 2,6-di-tert-
butylpyridine as a sterically hindered base to a mixture of diallyl
thioacetal 2c (chosen for stability reasons) and 10 mol% AuCl3
the reaction proceeded much slower, indicating that strongly
acidic conditions are required. This was further supported by
the fact that use of KAuCl4 under anhydrous conditions did not
result in any conversion (entry 22). It is known that alkynes can
mediate the reduction of trivalent gold to a complex of mono-
valent gold and tetrachloroaurate.15 Yet, this is unlikely to
occur here as both AuCl and KAuCl4 did not give better results
than AuCl3. Instead of HAuCl4, TfOH was selected as another
superacid to verify whether it could perform the desired trans-
formation as well.
1
2
3
4
5
6
7
8
40
165
40
40
40
40
40
40
40
20
20
20
20
20
20
20
20
20
20
20
20
20
1 d
60
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
65
37
60
—
—
48
—
a
—
Fe2(acac)3
CuI
TBAB
Ni(cod)2
PdCl2
AgOTf
p-TsOH
HOAc
H2SO4
HClO4
HBF4
BF3ÁEt2O
CuSO4
AuCl3
120
120
120
180
180
120
180
180
180
180
180
180
180
15
9
10
11
12
13
14
15
16
17
18
19
20
21
22
AuBr3
AuCl
15
60
180
180
60
AuOTf
AuClPPh3
HAuCl4
Curiously, the use of 10 mol% TfOH resulted in precisely
10% conversion to the desired benzo[c]thiophene. Repeating
the reaction with a quantitative amount of TfOH in CDCl3
to allow direct NMR-analysis revealed the formation of an
b
KAuCl4
180
a
b
Microwave heating. Anhydrous conditions.
Scheme 2 Proposed mechanism of the migratory cycloisomerization.
730 | Chem. Commun., 2015, 51, 729--732
This journal is ©The Royal Society of Chemistry 2015

View Article Online
ChemComm
Communication
intermediate product, which could be converted to the corre-
sponding benzo[c]thiophene by addition of Cs2CO3 or by aqueous
work-up. Based on the crude 1H, 13C, 19F, COSY and HSQC NMR
data, we postulate having trapped an intermediate as a covalently
bound triflate (Scheme 2, compound 7). This suggests that both
the strongly acidic conditions as well as the counterion play a
key role in the transformation. A sufficiently strong acid is able
to execute the migratory cycloisomerization but cannot catalyti-
cally form the desired benzo[c]thiophene, as the intermediate is
trapped by the counteranion. As such, the use of a catalytic
amount of AuCl3 under non-anhydrous conditions was selected
as the best option. Due to its highly hygroscopic nature, simply
weighing the catalyst in open air introduced enough moisture
for the reaction to proceed swiftly.
The proposed mechanism for benzo[c]thiophene formation
is depicted in Scheme 2. After acidic alkyne activation by in situ
formed HAuCl4, a 5-exo-dig cyclization takes place, furnishing
intermediate 5a which readily undergoes a Claisen rearrange-
ment to 6a. Instead of trapping 6a, as was the case for the
À
TfOH-mediated transformation, the AuCl4 counteranion does
not covalently bind to 6a. This allows for consecutive aromatiza-
tion to yield the desired benzo[c]thiophene 3a by elimination of a
proton, thus regenerating the catalyst. The concerted nature of
this Claisen-type rearrangement was confirmed by transforma-
tion of 2k to branched 3k, ruling out a fragmentative allyl shift.
Next, a solvent screen was performed to verify whether
CH2Cl2 indeed gave the best results in this case. Using strongly
apolar solvents (Table 2, entries 1 and 2) resulted in very long
reaction times, as did the use of highly polar solvents (entries 7–10).
Solvents of intermediate polarity gave more valuable results, with
Scheme 3 Ring closure of diallyl thioacetals 2. Catalyst loading, reaction
time and yield are indicated.
yields around 40% and reaction times of 3 hours (entries 3–6). In 65%, while lengthening the reaction time to 3 hours (entry 12).
dichloroethane (entry 5) the reaction was almost equally fast as As a compromise, a catalyst loading of 5–10 mol% was applied,
in dichloromethane, however, product degradation occurred depending on how fast the transformation proceeded (Scheme 3).
(which was clearly visible upon TLC analysis), resulting in an As product stability was clearly a determining factor in order to
isolated yield of only 43%. These observations established obtain good yields, an experiment was performed using 2,6-di-tert-
dichloromethane as the solvent of choice. The catalyst loading butyl-4-methylphenol (BHT) as a radical scavenging additive.
could be lowered to 1 mol%, maintaining an isolated yield of This attempt to further stabilize the end product proved to be
unsuccessful and the reaction yield was unchanged. For all
derivatives 2, except 2j, a conversion of Z98% was achieved based
Table 2 Screening of different solvents
on HPLC, though poor product stability led to losses during work-
up and purification.
The influence of electron-withdrawing groups on the migratory
cycloisomerization is mainly reflected in the improved stability of
the formed benzo[c]thiophenes. As for electron-donating groups
Loading
(equiv.)
Time
(min)
Yield
(%)
there is a large discrepancy in reaction time between 2f and 2g for
no apparent reason, while the 4-methoxybenzo[c]thiophene 3h is
obtained in excellent yield but only after 24 hours, possibly due to
steric hindrance. Thieno[3,4-b]thiophene 3i was obtained in 15%
yield over 2 steps. Non-terminal alkyne 2j could not be cyclized,
not even after 48 hours of reflux with 5 mol% AuCl3 in toluene,
and only starting material was recovered.
In conclusion, we have developed a 3-step approach to
benzo[c]thiophenes from commercially available ortho-halo
aromatic aldehydes. Sonogashira coupling and generation of
diallyl thioacetals 2 yielded suitable substrates for ring closure.
It was proven that a sufficiently strong acid can perform the
Entry
Solvent
1
2
3
4
5
6
7
8
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.01
0.05
Hexane
Toluene
EtOAc
DME
DCE
Acetone
DMF
CH3CN
1-Pentanol
MeOH
CH2Cl2
CH2Cl2
CH2Cl2
2 d
—
56
40
40
43
45
23
35
25
7
1.5 d
180
180
30
180
2.5 d
180
2.5 d
2.5 d
15
9
10
11
12
13
65
65
68
180
15
This journal is ©The Royal Society of Chemistry 2015
Chem. Commun., 2015, 51, 729--732 | 731

View Article Online
Communication
ChemComm
(e) L. Hairong, S. Sun, T. Salim, S. Bomma, A. C. Grimsdale and
Y. M. Lam, J. Polym. Sci., Part A: Polym. Chem., 2011, 50, 250;
( f ) A. Rajendran, T. Tsuchiya, S. Hirata and T. D. Iordanov, J. Phys.
Chem. A, 2012, 116, 12153; (g) B. M. Kobilka, A. V. Dubrovskiy,
M. D. Ewan, A. L. Tomlinson, R. C. Larock, S. Chaudhary and
M. Jeffries-El, Chem. Commun., 2012, 48, 8919; (h) Y. Zhen,
N. Obata, Y. Matsuo and E. Nakamura, Chem. – Asian J., 2012,
migratory cycloisomerization, but the consecutive benzo[c]thiophene
formation depends on the nature of the counteranion. Use of AuCl3
led to the in situ formation of HAuCl4 which efficiently catalyzed
the desired transformation. While it is often unclear whether
similar cycloisomerizations are proton- or metal-catalyzed, we
have clearly demonstrated that, in our case, a proton is the
catalytic species. However, the importance of the gold counter-
anion cannot be neglected. This approach has led to the desired
products 3 in 15–92% yields. A catalyst loading of 5–10 mol%
was considered optimal as a compromise between reaction time
and product stability. This approach could be applied to widely
substituted ortho-halobenzaldehydes and to heterocyclic cores as
well, however it is restricted to terminal alkynes. The obtained
benzo[c]thiophenes are mainly of interest as oligomers in
organic photovoltaic cells (OPV), along with a number of other
earlier discussed applications.
´
´
7, 2644; (i) C. O. Sanchez, J. C. Bernede, L. Cattin and F. R. Dıaz,
Synth. Met., 2011, 161, 2335; ( j) Q. Liu, F.-T. Kong, T. Okujima,
H. Yamada, S.-Y. Dai, H. Uno, N. Ono, X.-Z. You and Z. Shen,
Tetrahedron Lett., 2012, 53, 3264; (k) G. Long, X. Wan, P. Yun,
J. Zhou, Y. Liu, M. Li, M. Zhang and Y. Chen, Chin. J. Chem., 2013,
31, 1391; (l) S. Guenes, H. Neugebauer and N. S. Sariciftci, Chem. Rev.,
2007, 107, 1324.
´
7 (a) T.-Y. Chu, J. Lu, S. Beaupre, Y. Zhang, J.-R. Pouliot, S. Wakim,
J. Zhou, M. Leclerc, Z. Li, J. Ding and Y. Tao, J. Am. Chem. Soc., 2011,
133, 4250; (b) C. M. Amb, S. Chen, K. R. Graham, J. Subbiah,
C. E. Small, F. So and J. R. Reynolds, J. Am. Chem. Soc., 2011,
133, 10062; (c) S. C. Price, A. C. Stuart, L. Yang, H. Zhou and W. You,
J. Am. Chem. Soc., 2011, 133, 4625; (d) H. Zhou, L. Yang, A. C. Stuart,
S. C. Price, S. Liu and W. You, Angew. Chem., Int. Ed., 2011, 50, 2995.
8 R. H. L. Kiebooms, P. J. A. Adriaensens, D. J. M. Vanderzande and
J. M. J. V. Gelan, J. Org. Chem., 1997, 62, 1473.
9 S. Ito, T. Suzuki, T. Kawai and T. Iyoda, Synth. Met., 2000, 114, 235.
10 (a) N. Dieltiens and C. V. Stevens, Org. Lett., 2007, 9, 465; (b) T. S. A.
Heugebaert and C. V. Stevens, Org. Lett., 2009, 11, 5018; (c) T. S. A.
Heugebaert, L. P. D. Vervaecke and C. V. Stevens, Org. Biomol.
Chem., 2011, 9, 4791.
The authors are indebted to the Research Foundation
Flanders (FWO Vlaanderen) for financing pre- and postdoctoral
research.
Notes and references
11 For O and N analogues, see: (a) F. M. Istrate and F. Gagosz, Org. Lett.,
2007, 9, 3181; (b) F. M. Istrate and F. Gagosz, Beilstein J. Org. Chem.,
2011, 7, 878. For selected reviews, see: (c) A. S. Dudnik, N. Chernyak
and V. Gevorgyan, Aldrichimica Acta, 2010, 43, 37; (d) A. Corma,
1 D.-T. Hsu and C.-H. Lin, J. Org. Chem., 2009, 74, 9180.
2 (a) R. Jin and J. Zhang, J. Phys. Chem. A, 2013, 117, 8285;
(b) N. S. Kumar and A. K. Mohanakrishnan, Tetrahedron, 2010,
66, 5660; (c) N. S. Kumar, J. A. Clement and A. K. Mohanakrishnan,
Tetrahedron, 2009, 65, 822; (d) A. K. Mohanakrishnan, N. S. Kumar and
P. Amaladass, Tetrahedron Lett., 2008, 49, 4792; (e) A. K. Mohanakrishnan,
J. A. Clement, P. Amaladass and V. S. Thirunavukkarasu, Tetrahedron Lett.,
2007, 48, 8715.
´
A. Leyva-Perez and M. J. Sabater, Chem. Rev., 2011, 111, 1657;
(e) A. V. Gulevich, A. S. Dudnik, N. Chernyak and V. Gevorgyan,
Chem. Rev., 2013, 113, 3084; ( f ) N. T. Patil and Y. Yamamoto, Chem.
Rev., 2008, 108, 3395.
12 (a) C. Macleod, G. J. McKiernan, E. J. Guthrie, L. J. Farrugia, D. W.
Hamprecht, J. Macritchie and R. C. Hartley, J. Org. Chem., 2003,
68, 387; (b) M. Firouz, B. Ghasem and O. Afsane, Phosphorus, Sulfur
Silicon Relat. Elem., 2006, 181, 1445.
3 R. Jin, J. Fluorine Chem., 2014, 162, 26.
4 T. J. L. Silva, P. J. Mendes, M. H. Garcia, M. P. Robalo, J. P. P.
Ramalho, A. J. P. Carvalho, M. Buechert, C. Wittenburg and J. Heck,
Eur. J. Inorg. Chem., 2013, 3506.
13 (a) M. Jean, J. Renault, P. van de Weghe and N. Asao, Tetrahedron
Lett., 2010, 51, 378; (b) I. Nakamura, T. Sato and Y. Yamamoto, Angew.
Chem., Int. Ed., 2006, 45, 4473; (c) J. Li, K. Ji, R. Zheng, J. Nelson and
L. Zhang, Chem. Commun., 2014, 50, 4130; (d) P. W. Davies and S. J.-C.
Albrecht, Chem. Commun., 2008, 238.
5 (a) J. A. Clement, P. Gunasekaran and A. K. Mohanakrishnan,
Tetrahedron, 2009, 65, 4113; (b) S. T. Meek, E. E. Nesterov and
T. M. Swager, Org. Lett., 2008, 10, 2991.
6 (a) J. D. Douglas, G. Griffini, T. W. Holcombe, E. P. Young, O. P. Lee,
´
M. S. Chen and J. M. J. Frechet, Macromolecules, 2012, 45, 4069; (b) M. R.
Raj and S. Anandan, RSC Adv., 2013, 3, 14595; (c) M. Garcia, L. Fomina 14 A. S. K. Hashmi, Catal. Today, 2007, 122, 211.
and S. Fomine, Synth. Met., 2010, 160, 2515; (d) Y. Qin, J. Y. Kim, 15 (a) R. Huettel and H. Forkl, Chem. Ber., 1972, 105, 1664; (b) R. Huettel
C. D. Frisbie and M. A. Hillmyer, Macromolecules, 2008, 41, 5563;
and H. Forkl, Chem. Ber., 1972, 105, 2913.
732 | Chem. Commun., 2015, 51, 729--732
This journal is ©The Royal Society of Chemistry 2015