Synthesis of [1]benzothieno[3,2-b][1]benzothiophene (BTBT) and its higher homologs through palladium-catalyzed intramolecular decarboxylative arylation

Article abstract of DOI:10.1016/j.tetlet.2014.05.084

We report herein an effective method for the construction of 4- and 7-ring benzo-fused thieno[3,2-b]thiophenes, involving palladium-catalyzed intramolecular decarboxylative arylation as the key step.

Full text of DOI:10.1016/j.tetlet.2014.05.084

Tetrahedron Letters xxx (2014) xxx–xxx
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Tetrahedron Letters
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Synthesis of [1]benzothieno[3,2-b][1]benzothiophene (BTBT) and its
higher homologs through palladium-catalyzed intramolecular
decarboxylative arylation
Sojiro Minami a, Koji Hirano a, Tetsuya Satoh a,b, Masahiro Miura a,
⇑
a Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
b JST, ACT-C, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We report herein an effective method for the construction of 4- and 7-ring benzo-fused thieno[3,2-b]
thiophenes, involving palladium-catalyzed intramolecular decarboxylative arylation as the key step.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 14 April 2014
Revised 17 May 2014
Accepted 20 May 2014
Available online xxxx
Keywords:
Arylation
BTBT
Decarboxylation
Palladium
Thienoacene
Various poly-condensed arenes and heteroarenes are known to
work as organic semiconductors. Particularly, thienoacene-based
S
extended
p-systems have attracted much attention, as they are
S
robust and often show high hole mobilities in field effect transistor
(FET) devises.1 Benzo-fused thieno[3,2-b]thiophenes such as
[1]benzothieno[3,2-b][1]benzothiophene (BTBT) (Fig. 1) deriva-
tives are typical promising compounds. Thus, the synthesis of BTBT
and its derivatives has been studied extensively in recent years.
BTBT itself has been prepared by a number of methods including
the reactions of 1,2-bis(2-bromophenyl)acetylene with S8 or
Na2S,2 2,20-dichlorostilbene with Na2S,3 o-chlorobenzaldehyde
with NaSH,4 and benzyl chloride with S8.5,6 Another effective
method leading to BTBT is the iodine-promoted cyclization of
2,2’-bis(methylthio)stilbene, which was also applied to the synthe-
sis of a largely extended thienoacene, that is, bis[1]benzothie-
no[2,3-d;20,30-d0]benzo[1,2-b;4,5-b0]dithiophene (BBTBDT) and its
naphtho-analog.7 BBTBDT was also prepared by a Pummerer-type
biscyclization.8 Recently, Takimiya and co-workers disclosed an
elegant process for the construction of BTBT as well as its higher
homologs by the sequential reactions of 2[2-(trimethylsilyl)ethy-
nyl]thioanisole with PhSCl to form the corresponding 3-(pheny-
thio)benzo[b]thiophene and its 2-bromination followed by
palladium-catalyzed intramolecular C–H arylation.9 Despite these
BTBT
S
S
S
S
S
S
BBTBDT
S
S
iso-BBTBDT
Figure 1. Structure of BTBT, BBTBDT, and iso-BBTBDT.
achievements for constructing the BTBT series of compounds, there
still remains a substantial demand for further development of
effective and flexible synthetic methods to enhance their utility.
We herein describe a new synthetic sequence involving palla-
dium-catalyzed intramolecular decarboxylative arylation as the
key step, which enables to construct unknown bis[1]benzothie-
no[2,3-d;20,30-d0]benzo[1,2-b;5,6-b0]dithiophene (iso-BBTBDT) skel-
eton as well as BTBT and BBTBDT and their alkylated derivatives.
⇑
Corresponding author. Tel.: +81 6879 7360; fax: +81 6 6879 7362.
E-mail address: miura@chem.eng.osaka-u.ac.jp (M. Miura).
http://dx.doi.org/10.1016/j.tetlet.2014.05.084
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Minami, S.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.05.084

2
S. Minami et al. / Tetrahedron Letters xxx (2014) xxx–xxx
Decarboxylative arylation for constructing biaryl linkages using
widely available arenecarboxylic acids as one of the coupling part-
ners has recently emerged as an effective cross-coupling strategy
that complements the relevant conventional methods employing
arylmetal reagents.10
We previously reported the synthesis of 3-(arylthio)-2-aryl-
benzo[b]thiophene (4) of pharmaceutical interest (Scheme 1).
The method with the readily available methyl 3-chlorobenzo[b]thi-
ophene-2-carboxylate (1a) as the starting scaffold consists of
nucleophilic 3-arylthiolation and palladium-catalyzed decarboxy-
lative 2-arylation.11 This sequence may allow various 2,3-disubsti-
tution patterns on the benzo[b]thiophene framework. It may be
conceived that using 2-bromobenzenethiols could afford BTBT
and its derivatives via intramolecular decarboxylative arylation.
Consequently, we have undertaken to their synthesis based on this
strategy.
1)
Br
, K2CO3, DMFa
OTf
HS
R
CO2Me
2a: R = H, 2b: R = n-C8H17
S
2) KOH, EtOH-H2Ob
1b: X = OTf
Br
c
S
Pd(OAc)2
Ligand
S
R
R
)
CO2H
S
S
Base, DMAc
3a: R = H
: R = n-C8H17
5a
: R = H (BTBT
)
3b
BTBT
5b: R = n-C8H17 (C8-
Scheme 2. Synthesis of BTBT and its alkylated derivative (C8-BTBT). aConditions:
[1b]:[2]:[K2CO3] = 1:1.2:2 (7.1 mmol of 2a and 0.6 mmol of 2b were used), 80 °C, 8–
24 h in DMF under N2. bConditions: [2]:[KOH] = 1:3, EtOH/H2O = 10:1 (v/v), 100 °C,
6–14 h under N2. Yields of 3a and 3b were 53% and 65%, respectively (by two steps).
cSee Table 1.
We first examined the synthesis of mother BTBT by using methyl
3-[(trifluoromethyl)sulfonyloxy]-benzo[b]thiophene-2-carboxylate
(1b)12 as the starting material to test the applicability of the triflate
analog of 1a (Scheme 2), since the leaving group is required to con-
struct a higher BTBT analog (vide infra).
As expected, the reaction of 1b with 2-bromobenzenethiol (2a)
in the presence of potassium carbonate in DMF at 80 °C gave the
corresponding phenylthiolated product in 53% yield and the
subsequent hydrolysis with potassium hydroxide in ethanol/H2O
proceeded quantitatively to afford 3-[2-(bromophenyl)thio]-2-
benzo[b]thiophenecarboxylic acid (3a). Then, the intramolecular
decarboxylative arylation of 3a was conducted in the presence of
Pd(OAc)2 as catalyst in combination with a number of bases and
ligands in DMAc at 160 °C (Table 1). Using P(o-BP)Cy2 (o-BP =
biphenyl-2-yl, CyJohnphos) as ligand, various inorganic bases
including Cs2CO3, Na2CO3, K2CO3, and CsOAc could be used to fur-
nish BTBT in 71–77% yields (determined by GC, entries 1–4). The
relatively strong Cs2CO3 was found to be superior to the other
bases examined. However, a strong organic amine base, DABCO,
was far less effective (entry 5). PCy3 and P(o-BP)(t-Bu)2 (Johnphos)
in place of P(o-BP)Cy2 afforded higher BTBT yields of 90% and 91%,
respectively (entries 6 and 7). Thus, BTBT was isolated in 80% yield
in entry 7. Similarly, the use of 2-bromo-5-octylbenzenethiol
(2b)13 in place of 2a in the starting arylthiolation reaction of 1b
led to 2-octyl-BTBT 5b (C8-BTBT). The isolated yield of 5b in the
decarboxylative arylation step was 72% (entry 8). It is worth noting
that not only a dialkyl-BTBT, but also a monoalkyl-BTBT has been
reported to show a high hole mobility.6
Table 1
Synthesis of BTBT and C8-BTBT by intramolecular decarboxylative arylationa
Entry Substrate Ligandb
Base
Time (h) Product, yieldc (%)
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3a
P(o-BP)Cy2
P(o-BP)Cy2
P(o-BP)Cy2
P(o-BP)Cy2
P(o-BP)Cy2
PCy3
Cs2CO3
Na2CO3
K2CO3
CsOAc
DABCO
Cs2CO3
2
2
6
6
6
6
2
2
5a, 77
5a, 75
5a, 71
5a, 75
5a, 15
5a, 90
5a, 91 (80)
5b, (72)
3a
3a
P(o-BP)(t-Bu)2 Cs2CO3
P(o-BP)(t-Bu)2 Cs2CO3
3bd
a
Conditions: [3]:[Pd(OAc)2]:[P(o-BP)(t-Bu)2]:[Cs2CO3] = 1:0.1:0.2:2 (0.25 mmol
of 3 was used), at 160 °C under N2 in DMAc (2.1 mL).
b
o-BP = biphenyl-2-yl.
Determined by GC analysis. Value in parentheses is isolated yield.
0.13 mmol of 3b was used in 1 mL of DMAc.
c
d
OTf
S
EhO2C
CO2Eh
S
We next examined the synthesis of BBTBDT by using di(2-eth-
ylhexyl) 3,7-bis(trifluoromethanesulfonyloxy)benzo[1,2-b:4,5-b0]
dithiophene-2,6-carboxylate (1c) as the synthetic scaffold
(Scheme 3), the preparation of which starting from commercially
available 2,5-dibromoterephthalic acid was recently described by
us.12 The reaction of 1c with 2a followed by hydrolysis gave the
corresponding diacid 6a in 42% yield (by two steps) and the subse-
quent decarboxylative cyclization afforded BBTBDT in 61% yield
(18% after sublimation in vacuo). The physical properties of BBTBDT
Br
TfO
1c
(Eh = 2-ethylhexyl)
S
S
R
HO2C
CO2H
R
S
1) 2a or 2b, K2CO3, DMFa
S
2) KOH, EtOH-H2Ob
6a: R = H
6b
: R = n-C8H17
Br
c
S
Pd(OAc)2
S
Ar1
1) Ar1SH 2
K2CO3
Cl
S
P(o-BP)(t-Bu)2
R
R
S
S
Cs2CO3, DMAc
CO2Me
CO2H
S
2) KOH
S
S
7a: R = H (BBTBDT)
7b: R = n-C8H17 (2C8-BBTBDT)
3
Ar1
Ar2
1a
Pd cat., Ar2Br, Cs2CO3
Scheme 3. Synthesis of BBTBDT and 2C8-BBTBDT. aConditions: [1c]:[2]:[K2CO3] =
1:2.4:4 (3 mmol of 2a and 1.2 mmol of 2b were used), 80 °C, 18 h in DMF under N2.
bConditions: [2]:[KOH] = 1:6, EtOH/H2O = 5:1 (v/v), 100 °C, 15–21 h under N2.
Yields of 6a and 6b were 42% and 75%, respectively (by two steps). cConditions:
[6]:[Pd(OAc)2]:[P(o-BP)(t-Bu)2]:[Cs2CO3] = 1:0.2:0.4:4 (0.3 mmol of 6a and
0.114 mmol of 6b were used). Yields of 7a and 7b were 61% (18% after sublimation
in vacuo) and 26%, respectively.
S
4
Scheme 1. Preparation of 2-aryl-3-(arylthio)benzo[b]thiophene by nucleophilic
arylthiolation and decarboxylative arylation (previous work).11
Please cite this article in press as: Minami, S.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.05.084

S. Minami et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
2208; (d) Mei, J.; Diao, Y.; Appleton, A. L.; Fang, L.; Bao, Z. J. Am. Chem. Soc. 2013,
135, 6724; (e) Takimiya, K.; Nakano, M.; Kang, M. J.; Miyazaki, E.; Osaka, I. Eur. J.
Org. Chem. 2013, 217.
Cl
CO2Bu
Cl
S
S
2. (a) Sashida, H.; Yasuike, D. J. Heterocycl. Chem. 1998, 35, 725; (b) Li, Y.; Nie, C.;
Wang, W.; Li, X.; Verpoort, F.; Duan, C. Eur. J. Org. Chem. 2011, 7331.
3. Saito, M.; Yamamoto, T.; Osaka, I.; Miyazaki, E.; Takimiya, K.; Kuwabara, H.;
Ikeda, M. Tetrahedron Lett. 2010, 51, 5277.
BuO2C
1d
Br
Br
4. Saito, M.; Osaka, I.; Miyazaki, E.; Takimiya, K.; Kuwabara, H.; Ikeda, M.
Tetrahedron Lett. 2011, 52, 285.
S
S
1) 2a or 2b, K2CO3, DMF
5. Kosta, B.; Kozmik, V.; Svoboda, J. Collect. Czech. Chem. Commun. 2002, 67, 645.
6. Amin, A. Y.; Khassanov, A.; Reuter, K.; Meyer-Friedrichsen, T.; Halik, M. J. Am.
Chem. Soc. 2012, 134, 16548.
7. Yamamoto, T.; Nishimura, T.; Mori, T.; Miyazaki, E.; Osaka, I.; Takimiya, K. Org.
Lett. 2012, 14, 4914.
8. Yang, Y. S.; Yasuda, T.; Adachi, C. Bull. Chem. Soc. Jpn. 2012, 85, 1186.
9. Mori, T.; Nishimura, T.; Yamamoto, T.; Doi, I.; Miyazaki, E.; Osaka, I.; Takimiya,
K. J. Am. Chem. Soc. 2013, 135, 13900.
10. (a) Satoh, T.; Miura, M. Synthesis 2010, 3395; (b) Gooßen, L. J.; Rodríguez, N.;
Gooßen, K. Angew. Chem., Int. Ed. 2008, 47, 3100.
11. (a) Miyasaka, M.; Hirano, K.; Satoh, T.; Miura, M. Adv. Synth. Catal. 2009, 351,
2683; Corrigendum: (b) Miyasaka, M.; Hirano, K.; Satoh, T.; Miura, M. Adv.
Synth. Catal. 2012, 354, 957.
12. Ota, S.; Minami, S.; Hirano, K.; Satoh, T.; Ie, Y.; Seki, S.; Aso, Y.; Miura, M. RSC
Adv. 2013, 3, 12356.
13. The thiol 2b was prepared by a conventional sequence including acetylation,
nitration, reduction, and Sandmeyer reaction starting from commercially
available 4-octylaniline (a) Clemens, J. J.; Davis, M. D.; Lynch, K. R.; Macdonald,
T. L. Bioorg. Med. Chem. Lett. 2004, 14, 4903; (b) Cook, W. H.; Cook, K. H. J. Am.
Chem. Soc. 1933, 55, 1212; (c) Agou, T.; Kobayashi, J.; Kawashima, T. Chem. Eur.
J. 2007, 13, 8051.
14. Preparation of a dialkyl-BBTBDT by the sulfurization of a tetrahalo precursor
with S8 was described in a patent: Watanabe, M.; Ohashi, T.; Fujita, T. Jpn. Kokai
Tokkyo Koho, 2009, P2009–227670A.
S
S
2) KOH, EtOH
HO2C
CO2H
R
R
8a
8b
: R = H
: R = n-C8H17
S
S
Pd(OAc)2
R
R
S
S
P(o-BP)(t-Bu)2
9a: R = H (iso-BBTBDT)
9b: R = n-C8H17 (2C8-iso-BBTBDT)
Cs2CO3, DMAc
Scheme 4. Preparation of iso-BBTBDT and 2C8-iso-BBTBDT. aConditions:
[1d]:[2]:[K2CO3] = 1:2.4:4 (5.2 mmol of 2a and 1.6 mmol of 2b were used), 80 °C,
8 h in DMF under N2. bConditions: [2]:[KOH] = 1:6, EtOH/H2O = 5:1 (v/v), 100 °C,
15–21 h. Yields of 8a and 8b were 53% and 78%, respectively (by two steps).
cConditions: [8]:[Pd(OAc)2]:[P(o-BP)(t-Bu)2]:[Cs2CO3] = 1:0.2:0.4:4 (0.3 mmol of 8a
and 0.114 mmol of 8b were used). Yields of 9a and 9b were 56% (32% after
sublimation in vacuo) and 35% (25% after Soxhlet extraction), respectively.
have been reported.7,8 Using 1c and 2b could also be obtained 2,
15. Higa, T.; Krubsack, A. J. J. Org. Chem. 1975, 40, 3037; (b) Ried, W.; Oremek, G.;
Ocakcioglu, B. Liebigs Ann. Chem. 1980, 1424; (c) Maleševic´, M.; Karminsky-
9-dioctyl-BBTBDT (2C8-BBTBDT), albeit with a moderate yield.14
´
Zamola, G.; Bajic, M.; Boykin, D. D. Heterocycles 1995, 41, 2691.
Butyl
3,6-bis(chloro)benzo[2,1-b:3,4-b0]dithiophene-2,6-car-
16. Dibutyl
3,6-bis[(2-bromophenyl)thio]benzo[2,1-b:3,4-b0]dithiophene-2,7-
dicarboxylate (Scheme 4, the first step): In a 100 mL reaction flask were placed
the dichloride 1d (1.0 g, 2.18 mmol), the thiol 2a (0.61 mL, 5.2 mmol), K2CO3
(1.2 g, 8.7 mmol), and DMF (20 mL), and the resulting mixture was stirred for
24 h at 80 °C under nitrogen. The reaction was quenched by adding water,
extracted with chloroform, and dried over Na2SO4. Concentration followed by
purification by column chromatography with hexane/ethyl acetate (20:1, v/v)
gave the diarylthiolated diester (890 mg, 1.17 mmol, 53%) as a yellow solid. Mp
134–135 °C; 1H NMR (400 MHz, CDCl3) d 0.94 (t, J = 7.4 Hz, 6H), 1.42 (tq,
J = 7.6 Hz, 7.6 Hz, 4H), 1.70 (tt, J = 6.8 Hz, 6.8 Hz, 4H), 4.35 (t, J = 6.5 Hz, 4H),
6.58-6.61 (m, 2H), 6.93–7.00 (m, 4H), 7.52–7.55 (m, 2H), 7.75 (s, 2H); 13C NMR
(100 MHz, CDCl3) d 13.87, 19.35, 30.67, 66.31, 121.30, 122.80, 126.99, 127.92,
127.95, 130.66, 133.10, 134.35, 136.84, 137.93, 140.33, 161.41; HRMS (APCI)
m/z ([M+H]+) calcd for C32H29Br2O4S4: 764.9212, found: 764.9227.
boxylate (1d) was found to be a useful scaffold for constructing
an isomer of BBTBDT (iso-BBTBDT) 9a and its dioctyl derivative
9b (Scheme 4). Construction of the iso-BBTBDT skeleton is to date
unprecedented. Diester 1d can be readily prepared by the conve-
nient double ring-closure reaction of commercially available 1,4-
phenylenediacrylic acid with thionyl chloride in the presence of
pyridine followed by esterification with butanol.11,15 Decarboxyla-
tive cyclization of the intermediary diacids 8a and 8b, which were
prepared from 1d with 2a and 2b, gave rise to 9a and 9b in 56% and
36% yields, respectively.
In summary, we have demonstrated that 3-(chloro)- or 3-(trif-
luoromethanesulfonyloxy)-benzo[b]thiophene-2-carboxylic acid
esters in combination with 2-bromobenzenethiols are useful build-
ing-blocks for constructing BTBT and its higher homologs. Thus, by
using the present strategy including palladium-catalyzed decarb-
oxylative arylation as the key step, not only BTBT and BBTBDT,
but also a structurally new seven-ring theienoacene system, that
is, iso-BBTBDT can be constructed effectively.16 Further studies of
the synthesis of related derivatives by this reaction sequence and
their physical properties are underway and the details will be
reported in due course.
3,6-Bis[(2-bromophenyl)thio]benzo[2,1-b:3,4-b’]dithiophene-2,7-dicarboxylic acid
(8a): To a mixture of the diester (870 mg, 1.14 mmol) and KOH (384 mg,
6.84 mmol), water (2 mL), and ethanol (10 mL)-dioxane (4 mL) were
sequentially added, and the suspension was then heated at 100 °C for 6 h
under nitrogen. The resulting mixture was allowed to cool to room
temperature. The precipitate formed by addition of diluted aqueous HCl was
collected and washed with water, ethanol, and hexane, and then, dried under
high vacuum to provide dicarboxylic acid 8a (755 mg, 1.14 mmol, quant.) as a
yellow solid. Mp ca. 290 °C (decomposed); 1H NMR (400 MHz, DMSO-d6) d
6.55–6.58 (m, 2H), 7.03–7.06 (m, 4H), 7.52–7.57 (m, 2H), 7.62–7.64 (m, 2H),
14.13 (bs, 2H); 13C NMR (100 MHz, DMSO-d6) d 120.10, 122.09, 127.32, 127.60,
128.33, 128.46, 132.88, 133.35, 137.14, 138.46, 139.40, 161.72; HRMS (FABꢀ)
m/z (M+) calcd for C24H12Br2O4S4: 649.7980, found: 649.7996.
Bis[1]benzothieno[2,3-d;20,30-d0]benzo[1,2-b;5,6-b’]dithiophene (9a): In a 20 mL
two-necked flask were placed the diacid 8a (200 mg, 0.307 mmol), Pd(OAc)2
(14 mg, 0.061 mmol) and Johnphos (37 mg, 0.123 mmol), Cs2CO3 (407 mg,
1.23 mmol), and DMAc (5 mL). The resulting mixture was stirred for 7 h at
160 °C under nitrogen and cooled to room temperature. The solid in the
mixture was collected by filtration and washed with water, hexane, and
acetone to give 9a (69 mg, 0.171 mmol, 56%) as a yellow, practically insoluble
solid. This was further purified by sublimation in vacuo under heating to give
the analytical sample of 9a (39.1 mg, 0.097 mmol, 32%). Mp >300 °C; HRMS
(APCI) m/z ([M+H]+) calcd for C22H11S4: 402.9738, found: 402.9738; Anal. calcd
for C22H10S4: C, 65.64; H, 2.50. Found: C, 65.41; H, 2.63.
Acknowledgments
This work was partially supported by Grants-in-Aid for
Scientific Research from MEXT, JSPS, JST, Japan.
Supplementary data
2,9-Dioctylbis[1]benzothieno[2,3-d;20,30-d0]benzo[1,2-b;5,6-b0]dithiophene (9b):
This compound was prepared as above by using 8b (100 mg, 0.114 mmol).
The collected solid was washed with water, hexane, acetone, and finally with
chloroform to give 9b (24.8 mg, 0.040 mmol, 35%) as a sparingly soluble yellow
Supplementary data (characterization data of compounds) asso-
ciated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2014.05.084.
solid.
A further purification was made by Soxhlet extraction with
chlorobenzene to afford a somewhat clear colored sample of 9b (17.5 mg,
0.028 mmol 25%). Mp ca. 210 °C (decomposed); 1H NMR (400 MHz, toluene-d8
at 100 °C) d 0.90 (t, J = 6.4 Hz, 6H), 1.24–1.42 (m, 20H), 1.63 (tt, J = 6.4 Hz,
6.4 Hz, 4H), 2.61 (t, J = 7.4, 4H), 7.49 (s, 2H), 7.583 (s, 2H), 7.585 (d, J = 6.0 Hz,
2H) (one signal was overlapped by the solvent signal); HRMS (APCI) m/z
([M+H]+) calcd for C38H43S4: 627.2244, found: 627.2242.
References and notes
1. Recent reviews: (a) Murphy, A. R.; Fréchet, J. M. J. Chem. Rev. 2007, 107, 1066;
(b) Takimiya, K.; Shinamura, S.; Osaka, I.; Miyazaki, E. Adv. Mater. 2011, 23,
4347; (c) Wang, C.; Dong, H.; Hu, W.; Liu, Y.; Zhu, D. Chem. Rev. 2012, 112,
Please cite this article in press as: Minami, S.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.05.084