Synthesis of chalcogenophenes via cyclization of 1,3-diynes promoted by Iron(III) chloride and dialkyl dichalcogenides

Article abstract of DOI:10.1002/adsc.201401159

In this paper, we report the iron(III) chloride and dibutyl diselenide-mediated cyclization of 1,3-diynes which leads to 3,4-bis(butylselanyl)selenophenes. The optimization studies showed that the reaction was best performed with equimolar amounts of iron(III) chloride and dibutyl diselenide in dichloromethane at 40C for 4h. The method allows the synthesis of symmetrical and unsymmetrical selenophenes in moderate to good yields. A similar protocol was also extended to the synthesis of thiophene derivatives using dimethyl disulfide instead of dibutyl diselenide. The resulting selenophenes and thiophenes were further functionalized by selenium-halogen exchange reactions, Sonogashira cross-coupling reactions and electrophilic cyclizations.

Full text of DOI:10.1002/adsc.201401159

FULL PAPERS
DOI: 10.1002/adsc.201401159
Synthesis of Chalcogenophenes via Cyclization of 1,3-Diynes
Promoted by Iron(III) Chloride and Dialkyl Dichalcogenides
Filipe N. Bilheri,a Andrꢀ L. Stein,a and Gilson Zenia,*
a
Laboratꢁrio de Sꢂntese, Reatividade, Avaliażo Farmacolꢁgica e Toxicolꢁgica de OrganocalcogÞnios, CCNE,
Universidade Federal de Santa Maria, Santa Maria, Rio Grande do Sul 97105-900, Brazil
E-mail: gzeni@ufsm.br (homepage: http://www.ufsm.br)
Received: December 15, 2014; Revised: January 21, 2015; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201401159.
Abstract: In this paper, we report the iron(III) chlo- tocol was also extended to the synthesis of thiophene
ride and dibutyl diselenide-mediated cyclization of derivatives using dimethyl disulfide instead of dibutyl
1,3-diynes which leads to 3,4-bis(butylselanyl)seleno- diselenide. The resulting selenophenes and thio-
phenes. The optimization studies showed that the re- phenes were further functionalized by selenium–hal-
action was best performed with equimolar amounts ogen exchange reactions, Sonogashira cross-coupling
of iron(III) chloride and dibutyl diselenide in di- reactions and electrophilic cyclizations.
chloromethane at 408C for 4 h. The method allows
the synthesis of symmetrical and unsymmetrical sele- Keywords: cyclization; diorganyl diselenides; iron;
nophenes in moderate to good yields. A similar pro- selenophenes; thiophenes
Introduction
agents to active acyclic substrates to promote the in-
tramolecular cyclization[15] or to apply suitable cycli-
The use of organoselenium compounds in organic zation methodology to appropriate, previously pre-
synthesis has increased considerably because of their pared organoselenium substrates.[16] Many synthetic
ability to construct new chemical bonds in a highly se- methods, including electrophilic (halogens source)[17]
lective way, under mild reaction conditions,[1] and and transition metal-catalyzed reactions,[18] have been
their promising pharmacological applications as thera- successfully employed in the cyclization of organose-
peutic agents in the treatment of several diseases.[2] In lenium substrates. Nowadays, the most user-friendly
this field, selenophenes can be considered as one of system for the production of selenophene derivatives
the most important classes of organoselenium com- by using environmentally friendly, cost effective,
pounds. Examples of selenophenes and their deriva- green and mild methodologies has undergone an im-
tives have shown biological activities as antidepres- pressive increase of attention by chemists.[19] The iron
sant,[3] antioxidant,[4] anticonvulsant,[5] antibacterial,[6] reagents have appeared as an attractive alternative to
antitumoral,[7] antinociceptive[8] and anti-apoptotic other transition metals due to their relative stability,
agents.[9] Some of them exhibit an interesting profile abundance, low toxicity, economic and ecological ad-
of anti-inflammatory activity with a significant analge- vantages, and also excellent tolerance towards various
sic effect.[8] Apart from their biological activities, sele- functional groups.[20] It was shown that iron salts are
nophenes have also been used in the preparation of useful to catalyze the cross-coupling reaction of
materials that show potential as optical materials,[10] Grignard reagents with organic electrophiles,[21] to
semiconductors,[11] solar cells,[12] film transistors[13] and create new carbon–carbon, carbon–heteroatom and
energy storage applications.[14] Due to the growing im- heteroatom–heteroatom bonds[22] and recently they
portance and utility of these selenium heterocycles in have been applied to the synthesis of heterocycles as
organic synthesis, many new and remarkable findings well.[23] Our group and others have developed new ap-
and applications have been reported and considerable proaches involving the use of the combination of iron
efforts have been made to develop new methodolo- salts and diorganyl diselenides, as cyclizing agents, in
gies for their preparation. Traditional methods for the the preparation of heterocycles.[24] The main features
synthesis of selenophenes are based on the addition of the use of diorganyl diselenide reagents in the cy-
of either electrophilic or nucleophilic selenium re-
ACHTUNGTRENcNUGN lization reactions are their chemoselectivity and the
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢃ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
ÞÞ
These are not the final page numbers!

FULL PAPERS
Filipe N. Bilheri et al.
Table 1. Effect of different reaction parameters on the prep-
aration of selenophene 2a.[a]
Entry FeCl3
(equiv.)
Solvent Temp.
Time
[h]
Yield
[%]
[8C]
1
2
3
4
5
6
7
8
2
2
2
2
2
2
2
2
2
3
1.5
0.2
2
DCM
DCM
DCM
CH3CN 25
CH3CN 80
CH3NO2 100
DCE
CHCl3
THF
DCM
DCM
25
40
40
10
4
4
72
36
4
58
62[b]
81
–
38
59
40
64
–
Scheme 1. General scheme.
ability to incorporate both portions of diorganyl dise-
lenides (2 PhSe) in the final product, thus providing
a more useful and valuable method in terms of atom
economy. Concerning the reaction with iron salts and
diorganyl diselenides, a wide range of substrates were
readily converted into naphthalenes,[25] benzoxa-
zines,[26] indoles,[27] lactones,[28] isoxazoles,[29] chrome-
nones[30] and cyclobutanes.[31] Although we have ex-
plored the electrophilic cyclization of homopropargyl-
ic selenides and selenoenynes for the preparation of
selenophenes, both of these procedures are multistep,
as they require the previous preparation of the start-
ing materials.[32] The great versatility of the organose-
lenium moiety to construct new chemical bonds with
defined stereo-, regio-, and chemoselectivity led us to
explore if iron(III) chloride and diorganyl diselenides
could be used to promote the one-step synthesis of se-
lenophenes 2 from 1,3-diynes 1, avoiding the previous
preparation of selenoenynes 3 (Scheme 1).
80
60
60
40
40
4
2
9
12
4
16
24
4
10
11
12
13
56
48
–
DMSO 110
DCM 40
65[c]
[a]
The reaction was performed by the addition of BuSe-
AHCTUNGTERNNGSNU eBu to a solution of FeCl3 in CH2Cl2 (3 mL), at room
temperature, under an argon atmosphere. After 15 min,
at this temperature, the 1,3-diyne 1a (0.25 mmol) was
added. The resulting mixture was heated at 408C for 4 h.
The reaction was carried out under the ambient atmos-
phere.
[b]
[c]
The reaction was performed with 1.5 equiv. of BuSe-
AHCTUNGTERGSNNUN eBu.
chloromethane gave the best result in the formation
of selenophene 2a (Table 1, entries 4–9). The reaction
yields were not improved either by the use of larger
quantities of FeCl3 or catalytic amounts, even in the
Results and Discussion
The starting 1,3-diynes 1 were readily available by presence of DMSO which could restore the catalytic
using the process of homo- and cross-coupling of al- activity (Table 1, entries 10–12).[34] We propose that to
kynes and haloalkynes.[33] Firstly, we added the 1,4-di- obtain the products in maximum yields, the 1,3-diynes
phenylbuta-1,3-diyne 1a (0.25 mmol) to a mixture of 1a:dibutyl diselenide mol ratio should be 1:2. The use
FeCl3 (2 equiv.) and dibutyl diselenide (2 equiv.) of two equiv. of dibutyl diselenide gives four equiv. of
under an argon atmosphere with different reaction reactive BuSe; we postulate that three equiv. are in-
parameters to determine the best reaction conditions corporated in the final product and one equiv. acts as
(Table 1). For the reaction to take place in dichloro- a nucleophile in an SN2 reaction to remove the butyl
methane (3 mL) at room temperature, 10 h reaction group directly bonded to the selenium atom. To con-
time was necessary to provide selenophene 2a in 58% firm this assumption, we carried out the reaction
yield (Table 1, entry 1). When the reaction was car- using 1.5 equiv. of dibutyl diselenide (Table 1,
ried out under aerobic conditions and the reaction entry 13). The fact that the yield of the product de-
temperature was increased to 408C for 4 h, the yield creased indicates that the reaction requires more than
did improve (Table 2, entry 2). Although we carried 1.5 equiv. In addition, in all reactions which have
out many experiments using a catalytic amount of product formation, we detected the presence of
FeCl3 under aerobic conditions, to determine if the BuSeBu as a side-product. These two experiments
oxygen atom could be the mediator for catalyst regen- confirm that one BuSe anion acts as a nucleophile in
eration, an improvement in the reaction efficiency the cyclization.
was only obtained under an argon atmosphere
We further investigated the compatibility of a varie-
(Table 1, entry 3). Even though different solvents in- ty of 1,3-diynes 1 with dibutyl diselenide in the prepa-
cluding CH3CN, CH3NO2, DCE, CHCl3 and THF ration of several selenophenes 2. All reactions were
were rather effective, the reaction conducted in di- carried out following the optimized procedure de-
2
asc.wiley-vch.de
ꢃ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

FULL PAPERS
Synthesis of Chalcogenophenes via Cyclization of 1,3-Diynes
Table 2. Synthesis of selenophenes 2.[a,b]
[a]
The reaction was performed by the addition of BuSeSeBu (2 equiv.) to a solution of FeCl3 (2 equiv.) in CH2Cl2 (3 mL), at
room temperature, under an argon atmosphere. After 15 min the 1,3-diyne 1 (0.25 mmol) was added. The resulting mix-
ture was heated to 408C for 4 h.
Yields of purified products.
[b]
scribed in Table 1 entry 3: addition of ditubyl disele-
nide to a solution of iron(III) chloride in dichlorome-
thane, at room temperature, under an argon atmos-
phere. After 15 min the 1,3-diynes 1 were added. The
progress of the reaction of each substrate was moni-
tored by TLC to determine the necessary reaction
time for complete consumption of the starting materi-
al. We observed that 4 h was the required time for the
reactions to be completed. According to the results
shown in Table 2, the optimized conditions were com-
patible with a variety of symmetrical 1,3-diynes 1 pos-
sessing either electron-donating or electron-withdraw-
Scheme 2. Key intermediates for the cyclization of unsym-
metrical 1,3-diynes.
ing groups in the aromatic ring (Table 2, 2a–e). When
the reaction was carried out using the ortho-methylar-
yl and naphthyl groups the selenophenes 2f–h were
obtained in moderate yields, presumably due to the tion of unsymmetrical 1,3-diynes possesses two key in-
steric congestion around the triple bonds (Table 2, 2f– termediates which could be helpful to determine the
h). Although the substrate 1,3-diyne 1i has a deactivat- exact position of each selenium atom as well as which
ed alkyl group, it reacted under the optimized reac- selenium atom is responsible for the cyclization. One
tions to give the corresponding selenophene (Table 2, way of cyclization is the nucleophilic anti-attack of
2i). Besides, we examined the reactivity of unsymmet- the selenolate species at the C-1 of seleniranium ion I
rical 1,3-diyne derivatives that have the bifunctional giving the selenoenynes II, while the second anti-
alkyl and aryl groups directly bonded to the triple attack way takes place at the C-4 of seleniranium ion
bond. The cyclization of unsymmetrical 1,3-diynes 1j– III to give the selenoenynes IV (Scheme 2). The posi-
n afforded the corresponding selenophenes 2j–n in tive influence of the p bonds, from the aromatic rings
39–62% yields (Table 2, 2j–n). In the cyclization of next to the alkyne, is much stronger than the ones
unsymmetrical 1,3-diynes 1j–n two possible re- found in an alkyl chain. The aromatic ring increases
gioisomers could be obtained, but it is not possible to the electron density in the carbon–carbon bond induc-
determine them by final product analysis. However, ing the seleniranium ion I formation. Because of this
as indicated in Scheme 2, the first step of the cycliza- effect, the nucleophilic attack of the BuSe group is di-
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢃ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3
ÞÞ
These are not the final page numbers!

FULL PAPERS
Filipe N. Bilheri et al.
and diorganyl disulfides.[31] In this case, the addition
of a halogen source could be useful in the dissolution
of FeCl3 and breaking the polymeric FeCl3 to single
molecular form. Thus, we decide to test the influence
of the halogen source in the reaction medium. In our
case, when the reaction of 1,3-diynes 1a was conduct-
ed in the presence of NBS (2 equiv.), as additive,
using the previously optimized reaction conditions,
a mixture of thiophene product 4a with 4-bromothio-
phene 5a was obtained (Table 3, entries 1 and 2). In
the case where 0.5 equiv. of NBS was used the yields
of thiophene 4a increased up to 63% and only trace
of 5a was obtained (Table 3, entries 3 and 4). The
change of the NBS and FeCl3 amount showed no sig-
nificant improvement in the selectivity (Table 3, en-
tries 5–7). However, the change in the halogen source
from NBS to I2 (1.25 equiv.) and the use of FeCl3
(1.5 equiv.) provided the thiophene 4a product in
77% yields in the complete absence of 4-iodothio-
phene 5b (Table 3, entry 8). Furthermore, the reaction
also proceeded smoothly by reducing the quantity of
I2 to a catalytic amount affording good yields of the
desired thiophene 4a (Table 3, entries 9 and 10). After
the analysis of the above results, we selected the reac-
tion conditions described in Table 3, entry 10 as the
most consistent to extend the protocol to the prepara-
tion of other thiophenes 4 (Table 3).
Table 3. Effect of different reaction parameters on the prep-
aration of thiophene 4a.[a]
Entry MeSSMe
(equiv.)
Additive
(equiv.)
FeCl3
(equiv.)
Yield of 4/5
[%][b]
1
2
2
2
4
4
4
4
4
4
4
NBS (2)
NBS (2)
NBS (0.5)
NBS (0.5)
NBS (1.25)
NBS (4)
2
2
2
2
2
2
13/31
5/30
24/trace
63/trace
73/8
–/44
78/13
77/–
2[c]
3
4
5
6
7
8
9
10
NBS (1.25) 1.5
I2 (1.25)
I2 (0.5)
I2 (0.2)
1.5
1.5
1.5
76/–
77/–
[a]
The reaction was performed by the addition of the addi-
tive to a solution of MeSSMe in CH2Cl2 (3 mL), at room
temperature, under an argon atmosphere. After 10 min,
the FeCl3 was added and the solution was stirred for
15 min at room temperature and then 1,3-diyne 1a
(0.25 mmol) was added. The resulting mixture was
heated at 408C for 3 h.
[b]
[c]
Yields were determined by GC analysis.
The reaction was carried out at room temperature.
The optimized reaction conditions shown in
Table 1, entry 10 proved to be efficient and general
when applied to different 1,3-diynes. The results ob-
tained with the variations of 1,3-diynes are presented
rected to C-1 in the seleniranium ion I, next to the ar- in Table 4. The reaction allows the conversion of both
omatic ring, leading to selenoenynes II. Consequently, symmetrical aryl and alkyl 1,3-diynes to give the thio-
the selenium butyl group bonded to C-1 of the seleno- phene derivatives 4a–e in good yields; however, hin-
ACHTUNGTRENNUNGenynes II will promote the selenophene closure dered ortho-methylphenyl and deactivated alkyl
(Scheme 2). We also studied the effect of dimethyl groups, directly bonded to the carbon–carbon triple
and dibenzyl diselenides in this cyclization. When di- bond, gave moderate yields. We carried out the cycli-
methyl diselenide was used, there was no product ob- zation of unsymmetrical 1,3-diynes and found that the
tained. The reaction worked well with dibenzyl disele- expected thiophenes 4f–i were obtained in similar
nide; however, the product was lost by decomposition yields. We also investigated the effect of different di-
during the purification stage.
sulfides on the course of the cyclization. The reaction
In the sequence, our attention was focused on the worked well with diethyl disulfides for both symmetri-
application of the optimized reaction conditions cal and unsymmetrical 1,3-diynes (4k–m).
2
À
found in Table 1, entry 3 to the cyclization of 1,3-
Organoselenium substrates, which have a Csp Se
diynes by using dimethyl disulfide and dibutyl ditel- bond, were recognized as attractive starting materials
luride aiming to prepare thiophenes and telluro- for diverse transformations due to their region- and
phenes, respectively. In contrast to the dibutyl disele- stereoselectivity, mild reaction conditions and toler-
nide case, the iron-mediated cyclization of 1,3-diynes ance to many functional groups avoiding protection
1a in the presence of dibutyl ditelluride failed to give group chemistry.[7] The selenophenes prepared by our
the tellurophene, while the reaction with dimethyl di- methodology offer the possibility to introduce a halo-
sulfide gave only 31% yield of the thiophene 4a. Be- gen atom at C-3 and C-4 to the selenophene ring, via
cause of the low yield obtained in the synthesis of thi- selenium–halogen exchange reactions.[36] For this pro-
ophenes, we decided to review our early conditions to pose, we carried out the reaction of selenophene 2a
improve the yield of desired product 4a. As previous- with bromine (4 equiv.) in CHCl3 (5 mL) and after 4 h
ly observed, the combination of the stronger sulfur– under reflux the 3,4-dibromoselenophene 6 was ob-
sulfur bond with the energy of the iron–sulfur bond tained in 65% yield (Scheme 3). The potential appli-
could hamper the complex formation between iron cation of such derivatives is unquestionable because,
4
asc.wiley-vch.de
ꢃ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

FULL PAPERS
Synthesis of Chalcogenophenes via Cyclization of 1,3-Diynes
Table 4. Synthesis of thiophenes 4.[a]
[a]
The reaction was performed by the addition of I2 (20 mmol%) to a solution of MeSSMe (1 mmol) in CH2Cl2 (3 mL), at
room temperature, under an argon atmosphere. After 10 min, FeCl3 (0.375 mmol) was added and the solution was stirred
for 15 min at room temperature and then 1,3-diyne 1a (0.25 mmol) was added. The resulting mixture was heated at 408C
for the time indicated.
Yields of purified products.
EtSSEt (1 mmol) was used.
[b]
[c]
Scheme 3. Preparation of 3,4-dibromoselenophene 6.
2
À
as the Csp halogen bond finds applications in the
transition metal-catalyzed cross-coupling reactions
with nucleophilic compounds allowing the introduc-
Scheme 4. Preparation of 3-alkynylthiophene 7a and
thieno[3,4-b]thiophene 8a.
tion of various functional groups to the selenophene
2
À
ring. After proving the synthetic utility of the Csp
Se bond from selenophene 2, we planned the prepara-
tion of the thieno[3,4-b]thiophenes 8 aiming to test
the application of the thiophenes prepared. at room temperature, which afforded the thieno[3,4-
Thieno[3,4-b]thiophene-based polymers
have b]thiophene 8a in 40% yield (Scheme 4).[39]
emerged as attractive materials for both thin film In a final attempt to illustrate the potential applica-
transistors and solar cell devices.[37] Our exploration tion of the chalcogenophenes prepared, we decided to
begun with a sequential palladium cross-coupling and use the thiophene 4a as staring material in the prepa-
cyclization reaction using 3-bromo-4-(methylthio)thio- ration of dibenzo[d,d’]thieno[3,2-b;4,5-b’]-dithiophene
phene 5a, as starting material obtained under the op- (DBTDT) 9, which has been recently proposed for
timized reaction conditions (Table 3, entry 6). The So- high-performance organic film-effect transistors and
nogashira cross-coupling reaction of 3-bromo-4- for their high ionization potential and photostabili-
(methylthio)thiophene 5a with propargyl alcohol, af- ty.[40] Thus, DBTDT 9 was prepared in 83% overall
forded the 3-alkynylthiophene 7a in 63% yield yield via oxidation of thiophene 4a to the sulfoxide
(Scheme 4).[38] Afterward, the cyclization step was derivative followed by its cyclization promoted by
achieved by the reaction of 7a with iodine in CH2Cl2 CF3SO3H (Scheme 5).[41]
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢃ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
5
ÞÞ
These are not the final page numbers!

FULL PAPERS
Filipe N. Bilheri et al.
cooled to room temperature, dissolved in ethyl acetate and,
washed with a saturated solution of NH4Cl, dried with
MgSO4, and concentrated under vacuum. The residue was
purified by column chromatography over silica gel, using
hexane as eluent to provide the 3,4-bis(butylselanyl)-seleno-
phenes 2.
3,4-Bis(butylselanyl)-2,5-diphenylselenophene (2a): Ob-
tained as a yellow oil; yield: 0.111 g (81%). 1H NMR
(CDCl3, 200 MHz): d?7.61–7.56 (m, 4H), 7.45–7.33 (m, 6H),
2.63 (t, J=7.2 Hz, 4H), 1.43 (quint, J=7.8 Hz, 4H), 1.19
(sex, J=7.48 Hz, 4H), 0.76 (t, J=7.2 Hz, 6H); 13C NMR
(CDCl3, 50 MHz): d=136.8, 129.7, 128.9, 128.1, 127.9, 31.7,
29.5, 22.6, 13.5; MS (EI, 70 eV): m/z (relative intensity)=
554 [M+1] (23), 360 (53), 282 (100), 202 (99), 57(16); HR-
MS (ESI-TOF): m/z=556.9771, calcd. for C24H29Se3 (M+
H+): 556.9765.
Scheme 5. Preparation of dibenzo[d,d’]thieno[3,2-b;4,5-b’]-
dithiophene (DBTDT) 9.
Conclusions
We have developed in this work a two-step, one-pot
protocol for the direct cyclization of 1,3-diynes into
selenophenes. This was promoted by iron(III) chlo-
ride and dibutyldiselenide avoiding the prior prepara-
tion of selenoenyne substrates or unstable and air-sen-
sitive selenolate anions. The essential role of equimo-
lar amounts of iron(III) chloride and dibutyl disele-
nide to the cyclization was described. In this regard,
the results of the optimization process indicated that
the use of the mole rati 1:2 of 1,3-diynes:dibutyl dise-
lenide was required for the reactions in order to ach-
ieve the maximum yields. Considering that two equiv.
of dibutyl diselenide give four portions of the reactive
species BuSe, we concluded that three portions were
incorporated in the final product and one portion
acted as a nucleophile in an SN2 reaction to remove
the butyl group directly bonded to the selenium atom.
Our cyclization methodology was stereoselective, pro-
viding exclusively the desired E-selenoenynes as inter-
mediates, which form the selenophene via an intramo-
lecular 5-endo-dig cyclization. The positive influence
of the p bonds, from the aromatic rings next to the
alkyne, increases the electron density in the carbon–
carbon bond inducing the stereoselectivity in the cy-
3,4-Bis(butylselanyl)-2,5-di-para-tolylselenophene
(2b):
Obtained as a yellow oil; yield: 0.107 g (74%). 1H NMR
(CDCl3, 200 MHz): d=7.49 (d, J=8.0 Hz, 4H), 7.23 (d, J=
7.8 Hz, 4H), 2.67 (t, J=7.2 Hz, 4H), 2.41 (s, 6H), 1.47
(quint, J=7.6 Hz, 4H), 1.24 (sex, J=7.4 Hz, 4H), 0.8 (t, J=
7.2 Hz, 6H); 13C NMR (CDCl3, 50 MHz): d=149.9, 137.8,
137.7, 134.1, 129.6, 128.8, 128.6, 31.9, 29.6, 22.8, 21.3, 13.5;
MS (EI, 70 eV): m/z (relative intensity)=582 [M+1] (20),
389 (34), 310 (100), 230 (30), 206 (12); HR-MS (ESI-TOF):
m/z=585.0083, calcd. for C26H33Se3 (M+H+): 585.0078.
3,4-Bis(butylselanyl)-2,5-bis(4-methoxyphenyl)seleno-
phene (2c): Obtained as a yellow oil; yield: 0.093 g (61%).
1H NMR (CDCl3, 200 MHz): d=7.51 (d, J=8.8 Hz, 2H),
6.96 (d, J=8.8 Hz, 2H), 3.85 (s, 6H), 2.64 (t, J=7.2 Hz,
4H), 1.45 (quint, J=7.1 Hz, 4H), 1.21 (sex, J=7.9 Hz, 4H),
0.78 (t, J=7.2 Hz, 6H); 13C NMR (CDCl3, 100 MHz): d=
136.8, 129.7, 128.9, 128.1, 127.9, 31.7, 29.5, 22.6, 13.5; MS
(EI, 70 eV): m/z (relative intensity)=554 [M+1] (23), 360
(53), 282 (100), 202 (99), 57(16); HR-MS (ESI-TOF): m/z=
556.9771, calcd. for C26H33O2Se3 (M+H+): 556.9765.
3,4-Bis(butylselanyl)-2,5-bis(4-chlorophenyl)selenophene
(2d): Obtained as a brown solid; yield: 0.108 g (68%); mp
40–428C. 1H NMR (CDCl3, 200 MHz): d=7.54–7.51 (m,
4H), 7.40–7.37 (m, 4H), 2.67 (t, J=7.2 Hz, 4H), 1.46 (quint,
J=7.5 Hz, 4H), 1.24 (sex, J=7.4 Hz, 4H), 0.80 (t, J=
7.3 Hz, 6H); 13C NMR (CDCl3, 50 MHz): d=148.8, 135.2,
134.1, 131.1, 128.4, 31.9, 29.9, 22.9, 13.3; MS (EI, 70 eV): m/
z (relative intensity)=624 [M+1] (15), 429 (55), 350 (100),
270 (64), 200 (58), 57 (50); HR-MS (ESI-TOF): m/z=
624.8987, calcd. for C24H27Cl2Se3 (M+H+): 624.8985.
ACHTUNGTRENNUNGclization. The versatility of these chalcogenophenes
was also studied for the selenium–halogen exchange
reaction, Sonogashira cross-coupling reaction and
electrophilic cyclization reaction. In addition the sele-
nenophene prepared was also applied as starting ma-
terial in the preparation of a thin film transistor
device structure. Furthermore, another feature of this
protocol is the fact that the reactions were carried out
using iron salts, which are readily commercially avail-
able, less expensive and relatively less toxic.
General Procedure for Iron-Promoted Cyclization of
Diynes and Diorganoyl Disulfide
To a Schlenk tube, under an argon atmosphere, containing
the appropriate diorganoyl disulfide (4 equiv.) in dry CH2Cl2
(3 mL) was added iodine or NBS (20 mol%). The resulting
solution was stirred for 5 min at room temperature. After
this time, FeCl3 (1.5 equiv.) was added and the resulting mix-
ture was stirred for additional 15 min. To this solution was
added the appropriate diyne (0.25 mmol) in CH2Cl2 (1 mL)
and resulting solution was stirred under 408C for the time
indicated in Table 4. The mixture was cooled to room tem-
perature, dissolved in ethyl acetate and, washed with a satu-
rated solution of NH4Cl, dried with MgSO4, and concentrat-
ed under vacuum. The residue was purified by column chro-
Experimental Section
General Procedure for Iron-Promoted Cyclization of
Diynes and Dibutyl Diselenides
To a Schlenk tube, under an argon atmosphere, containing
FeCl3 (2 equiv.) in dry CH2Cl2 (3 mL) was added the dibutyl
diselenide (2 equiv.). The resulting solution was stirred for
10 min at room temperature. After this the appropriate
diyne (0.25 mmol) was added in CH2Cl2 (1 mL) and the re-
sulting solution was stirred for 4 h at 408C. The mixture was
6
asc.wiley-vch.de
ꢃ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

FULL PAPERS
Synthesis of Chalcogenophenes via Cyclization of 1,3-Diynes
matography over silica gel, using hexane as eluent to pro-
vide the 3,4-bis(methylthio)-thiophenes 4.
Angew. Chem. 2009, 121, 8559–8562; Angew. Chem.
Int. Ed. 2009, 48, 8409–8411; h) S. Santoro, B. Battistel-
li, L. Testaferri, M. Tiecco, C. Santi, Eur. J. Org. Chem.
2009, 4921–4925; i) M. Tiecco, L. Testaferri, F. Marini,
S. Sternativo, F. Del Verme, C. Santi, L. Bagnoli, A.
Temperini, Tetrahedron 2008, 64, 3337–3342.
[2] a) V. Nascimento, E. E. Alberto, D. W. Tondo, D. Dam-
browski, M. R. Detty, F. Nome, A. L. Braga, J. Am.
Chem. Soc. 2012, 134, 138–141; b) C. W. Nogueira,
J. B. T. Rocha, Arch. Toxicol. 2011, 85, 1313–1359;
c) M. Soriano-Garcia, Curr. Med. Chem. 2004, 11,
1657–1669.
[3] B. M. Gai, A. L. Stein, J. A. Roehrs, F. N. Bilheri, C. W.
Nogueira, G. Zeni, Org. Biomol. Chem. 2012, 10, 798–
807.
[4] R. F. Schumacher, A. R. Rosꢄrio, A. C. G. Souza, C. I.
Acker, C. W. Nogueira, G. Zeni, Bioorg. Med. Chem.
2011, 19, 1418–1425.
[5] E. A. Wilhelm, B. M. Gai, A. C. G. Souza, C. F. Borto-
latto, J. A. Roehrs, C. W. Nogueira, Mol. Cell. Biochem.
2012, 365, 175–180.
[6] J. A. Wiles, A. S. Phadke, B. J. Bradbury, M. J. Pucci,
J. A. Thanassi, M. Deshpande, J. Med. Chem. 2011, 54,
3418–3425.
[7] a) E. A. Wilhelm, C. R. Jesse, M. Prigol, D. Alves, R. F.
Schumacher, C. W. Nogueira, Cell. Biol. Toxicol. 2010,
26, 569–577; b) E. A. Wilhelm, C. R. Jesse, C. F. Borto-
latto, C. W. Nogueira, L. Savegnago, Brain. Res. Bull.
2009, 79, 281–287.
[8] E. A. Wilhelm, C. R. Jesse, C. F. Bortolatto, C. W. No-
gueira, L. Savegnago, Pharmacol. Biochem. Behav.
2009, 93, 419–425.
3,4-Bis(methylthio)-2,5-diphenylthiophene (4a): Obtained
as a brown solid; yield: 0.056 g (69%); mp 83–858C.
1H NMR (CDCl3, 200 MHz): d=7.76–7.74 (m, 4H), 7.51–
7.41 (m, 6H), 2.36 (s, 6H); 13C NMR (CDCl3, 50 MHz): d=
144.1, 133.9, 133.1, 129.4 128.5, 128.3, 132.3, 19.9; MS (EI,
70 eV): m/z (relative intensity)=328 [M+1] (100), 265 (51),
233 (13), 77 (4); HR-MS (ESI-TOF): m/z=329.0499, calcd.
for C18H25S3 (M+H+): 328.0417.
2,5-Bis(4-fluorophenyl)-3,4-bis(methylthio)thiophene (4b):
Obtained as a brown solid; yield: 0.057 g (63%); mp 106–
1
1088C. H NMR (CDCl3, 200 MHz): d=7.66–7.63 (m, 4H),
7.15–7.11 (m, 4H) 2.29 (s, 6H); 13C NMR (CDCl3, 50 MHz):
d=162.8 (d, J=248.7 Hz), 142.9, 133.3, 131.1 (d, J=8.3 Hz),
129.7 (d, J=3.2 Hz), 115.5 (d, J=21.7 Hz); MS (EI, 70 eV):
m/z (relative intensity)=364 [M+1] (100), 302 (78), 270
(34), 138 (49), 73 (16); HR-MS (ESI-TOF): m/z=365.0307,
calcd. for C18H15F2S3 (M+H+): 365.0304.
3,4-Bis(methylthio)-2,5-di-ortho-tolylthiophene (4c): Ob-
tained as a brown oil; yield: 0.045 g (51%). 1H NMR
(CDCl3, 200 MHz): d=7.35–7.23 (m, 8H), 2.30 (s, 6H), 2.20
(s, 6H); 13C NMR (CDCl3, 50 MHz): d=142.9, 137.8, 133.3,
133.3, 132.9, 131.1, 130.1, 128.8, 125.4, 29.6; MS (EI, 70 eV):
m/z (relative intensity)=356 [M+1] (25), 324 (100), 309
(44), 243 (21), 130 (10); HR-MS (ESI-TOF): m/z=357.0807,
calcd. for C20H21S3 (M+H+): 357.0805.
2,5-Dibutyl-3,4-bis(methylthio)thiophene (4d): Obtained
as a yellow oil; yield: 0.041 g (58). 1H NMR (CDCl3,
200 MHz): d=2.94 (t, J=7.8 Hz, 4H), 2.32 (s, 6H), 1.61
(quint, J=7.2 Hz, 4H), 1.40 (sex, J=7.2 Hz, 4H), 0.94 (t,
J=7.2 Hz, 6H); 13C NMR (CDCl3, 50 MHz): d=145.8,
131.2, 33.8, 29.2, 22.3, 20.2, 13.8; MS (EI, 70 eV): m/z (rela-
tive intensity)=288 [M+1] (100), 245 (77), 202 (33), 187
(20); HR-MS (ESI-TOF): m/z=289.1122, calcd. for C14H25S3
(M+H+): 289.1118.
[9] S. H. Juang, C. C. Lung, P. C. Hsu, K. S. Hsu, Y. C. Li,
P. C. Hong, H. S. Shiah, C. C. Kuo, C. W. Huang, Y. C.
Wang, L. Huang, T. S. Chen, S. F. Chen, K. C. Fu, C. L.
Hsu, M. J. Lin, C. J. Chang, C. L. Ashendel, T. C. K.
Chan, K. M. Chou, J. Y. Chang, Mol. Cancer. Ther.
2007, 6, 193–202.
[10] J. Hollinger, A. A. Jahnke, N. Coombs, D. S. Seferos, J.
Acknowledgements
Am. Chem. Soc. 2010, 132, 8546–8547.
[11] Y.-J. Hwang, N. M. Murari, S. A. Jenekhe, Polym.
Chem. 2013, 4, 3187–3195.
[12] D. Gao, J. Hollinger, D. S. Seferos, ACS Nano 2012, 6,
7114–7121.
We are grateful to FAPERGs, CAPES and CNPq for the fi-
nancial support. CNPq is also acknowledged for the fellow-
ships.
[13] A. K. Mohanakrishnan, N. S. Kumar, P. Amaladass, Tet-
rahedron Lett. 2008, 49, 4792–4795.
[14] A. A. Jahnke, B. Djukic, T. M. McCormick, E. B. Dom-
ingo, C. Hellmann, Y. Lee, D. S. Seferos, J. Am. Chem.
Soc. 2013, 135, 951–954.
References
[1] a) J. B. Azeredo, M. Godoi, G. M. Martins, C. C. Sil-
veira, A. L. Braga, J. Org. Chem. 2014, 79, 4125–4130;
b) A. Nomoto, A. Ogawa, in: The Chemistry of Organ-
ic Selenium and Tellurium Compounds, (Ed.: Z. Rap-
poport), John Wiley & Sons, Chichester, 2012, Vol. 3,
pp 623–688; c) C. Santi, S. Santoro, in: Organoselenium
Chemistry: Synthesis and Reactions, (Ed.: T. Wirth),
Wiley-VCH, Weinheim, 2011, pp 1–51; d) M. Senatore,
A. Lattanzi, S. Santoro, G. Della Sala, Org. Biomol.
Chem. 2011, 9, 6205–6207; e) C. Santi, S. Santoro, B.
Battistelli, Curr. Org. Chem. 2010, 14, 2442–2462; f) G.
Perin, E. J. Lenard¼o, R. G. Jacob, R. B. Panatieri,
Chem. Rev. 2009, 109, 1277–1301; g) D. M. Freuden-
dahl, S. Santoro, S. A. Shahzad, C. Santi, T. Wirth,
[15] a) P. Maity, D. Kundu, R. Roy, B. C. Ranu, Org. Lett.
2014, 16, 4122; b) F. Shibahara, R. Sugiura, T. Murai,
Org. Lett. 2009, 11, 3064–3067; c) T. Murai, A. Fujishi-
ma, C. Iwamoto, S. Kato, J. Org. Chem. 2003, 68, 7979–
7982; d) T. Murai, M. Ishizuka, A. Suzuki, S. Kato, Tet-
rahedron Lett. 2003, 44, 1343–1346; e) T. Murai, M.
Maeda, F. Matsuoka, T. Kanda, S. Kato, Chem.
Commun. 1996, 1461–1462.
[16] a) K. O. Hessian, B. L. Flynn, Org. Lett. 2003, 5, 4377–
4380; b) B. L. Flynn, P. Verdier-Pinard, E. Hamel, Org.
Lett. 2001, 3, 651–654.
[17] a) S. A. Worlikar, R. C. Larock, Org. Lett. 2009, 11,
2413–2416; b) S. A. Worlikar, T. Kesharwani, T. Yao,
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢃ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
7
ÞÞ
These are not the final page numbers!

FULL PAPERS
Filipe N. Bilheri et al.
R. C. Larock, J. Org. Chem. 2007, 72, 1347–1353; c) T.
Kesharwani, S. A. Worlikar, R. C. Larock, J. Org.
Chem. 2006, 71, 2307–2312.
[26] A. L. Stein, F. N. Bilheri, D. F. Back, G. Zeni, Adv.
Synth. Catal. 2014, 356, 501–508.
[27] A. SperanÅa, B. Godoi, P. H. Menezes, G. Zeni, Synlett
2013, 24, 1125–1132.
[28] S. Kumar, J.-C. P. Helt, J. Autschbach, M. R. Detty, Or-
ganometallics 2009, 28, 3426–3436.
[18] a) S. S. Worlikar, R. C. Larock, Curr. Org. Chem. 2011,
15, 3214–3232; b) S. A. Worlikar, R. C. Larock, J. Org.
Chem. 2009, 74, 9132–9139.
[19] a) D. Gartner, A. Welther, B. R. Rad, R. Wolf, A. Jaco-
bi von Wangelin, Angew. Chem. 2014, 126, 3796–3800;
Angew. Chem. Int. Ed. 2014, 53, 3722–3726; b) T. N.
Gieshoff, A. Welther, M. T. Kessler, M. H. G. Prechtl,
A. Jacobi von Wangelin, Chem. Commun. 2014, 50,
2261–2264; c) A. Welther, A. Jacobi von Wangelin,
Curr. Org. Chem. 2013, 17, 326–335; d) W. M. Czaplik,
[29] A. Speranca, B. Godoi, G. Zeni, J. Org. Chem. 2013,
78, 1630–1637.
[30] B. Godoi, A. SperanÅa, C. A. Bruning, D. F. Back, P. H.
Menezes, C. W. Nogueira, G. Zeni, Adv. Synth. Catal.
2011, 353, 2042–2050.
[31] L. Yu, L. Ren, R. Yi, Y. Wu, T. Chen, R. Guo, J. Orga-
nomet. Chem. 2011, 696, 2228–2233.
ˇ
M. Mayer, J. Cvengros, A. Jacobi von Wangelin, Chem-
[32] a) R. F. Schumacher, A. R. Rosario, A. C. G. Souza,
P. H. Menezes, G. Zeni, Org. Lett. 2010, 12, 1952–1955;
b) A. L. Stein, D. Alves, J. T. D. Rocha, C. W. Nogueira,
G. Zeni, Org. Lett. 2008, 10, 4983–4986; c) D. Alves, C.
Luchese, C. W. Nogueira, G. Zeni, J. Org. Chem. 2007,
72, 6726–6734.
[33] a) X. Meng, C. Li, B. Han, T. Wang, B. Chen, Tetrahe-
dron 2010, 66, 4029–4031; b) D. Li, K. Yin, J. Li, X. Jia,
Tetrahedron Lett. 2008, 49, 5918–5919; c) P. Siemsen,
R. C. Livingston, F. Diederich, Angew. Chem. 2000,
112, 2740–2767; Angew. Chem. Int. Ed. 2000, 39, 2632–
2657; d) Y. Nishihara, K. Ikegashira, A. Mori, T.
Hiyama, Tetrahedron Lett. 1998, 39, 4075–4078.
[34] A. R. Suarez, A. M. Baruzzi, L. I. Rossi, J. Org. Chem.
1998, 63, 5689–5691.
[35] A. Eichhofer, G. Buth, F. Dolci, K. Fink, R. A. Mole,
P. T. Wood, Dalton Trans. 2011, 40, 7022–7032.
[36] A. D. Palkowitz, A. L. Glasebrook, K. J. Thrasher,
K. L. Hauser, L. L. Short, D. L. Phillips, B. S. Muehl,
M. Sato, P. K. Shetler, G. J. Cullinan, T. R. Pell, H. U.
Bryant, J. Med. Chem. 1997, 40, 1407–1416.
SusChem 2009, 2, 396–417; e) C. Bolm, J. Legros, J. L.
Paih, L. Zani, Chem. Rev. 2004, 104, 6217–6254.
[20] A. O. Abdelwareth, A. A. O. Sarhan, C. Bolm, Chem.
Soc. Rev. 2009, 38, 2730–2744.
[21] a) A. Fꢅrstner, A. Schlecker, C. W. Lehmann, Chem.
Commun. 2007, 4277–4279; b) G. Seidel, D. Laurich, A.
Fꢅrstner, J. Org. Chem. 2004, 69, 3950–3952; c) A.
Fꢅrstner, A. Leitner, M. Mendez, H. Krause, J. Am.
Chem. Soc. 2002, 124, 13856–13863; d) A. Fꢅrstner, A.
Leitner, Angew. Chem. 2002, 114, 632–635; Angew.
Chem. Int. Ed. 2002, 41, 609–612.
[22] a) A. Correa, O. G. Mancheno, C. Bolm, Chem. Soc.
Rev. 2008, 37, 1108–1117; b) O. Bistri, A. Correa, C.
Bolm, Angew. Chem. 2008, 120, 596–598; Angew.
Chem. Int. Ed. 2008, 47, 586–588; c) A. Correa, M.
Carril, C. Bolm, Angew. Chem. 2008, 120, 2922–2925;
Angew. Chem. Int. Ed. 2008, 47, 2880–2883; d) A.
Correa, C. Bolm, Angew. Chem. 2007, 119, 9018–9021;
Angew. Chem. Int. Ed. 2007, 46, 8862–8865.
[23] K. C. Majumdar, N. De, T. Ghosh, B. Roy, Tetrahedron
2014, 70, 4827–4868.
[37] P. Sonar, S. P. Singh, Y. Li, M. S. Soh, A. Dodabalapur,
[24] a) A. Speranca, B. Godoi, S. Pinton, D. F. Back, P. H.
Menezes, G. Zeni, J. Org. Chem. 2011, 76, 6789–6797;
b) H.-A. Du, R.-Y. Tang, C.-L. Deng, Y. Liu, J.-H. Li,
X.-G. Zhang, Adv. Synth. Catal. 2011, 353, 2739–2748;
c) R. M. Gay, F. Manarin, C. C. Schneider, D. A. Baran-
celli, M. D. Costa, G. Zeni, J. Org. Chem. 2010, 75,
5701–5706.
Adv. Mater. 2010, 22, 5409–5413.
[38] K. Hirano, Y. Inaba, K. Takasu, S. Oishi, Y. Takemoto,
N. Fujii, H. Ohno, J. Org. Chem. 2011, 76, 9068–9080.
[39] S. Mehta, J. P. Waldo, R. C. Larock, J. Org. Chem. 2009,
74, 1141–1147.
[40] L. Alessandrini, D. Braga, A. Jaafari, L. Miozzo, S.
Mora, L. Silvestri, S. Tavazzi, A. Yassar, J. Phys. Chem.
A 2011, 115, 225–231.
[25] Z.-J. Yang, B.-L. Hu, C.-L. Deng, X.-G. Zhang, Adv.
Synth. Catal. 2014, 356, 1962–1966.
[41] J. Gao, Y. Li, Z. Wang, Org. Lett. 2013, 15, 1366–1369.
8
asc.wiley-vch.de
ꢃ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

FULL PAPERS
Synthesis of Chalcogenophenes via Cyclization of 1,3-
Diynes Promoted by Iron(III) Chloride and Dialkyl
Dichalcogenides
9
Adv. Synth. Catal. 2015, 357, 1 – 9
Filipe N. Bilheri, Andrꢀ L. Stein, Gilson Zeni*
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢃ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
9
ÞÞ
These are not the final page numbers!