5-Substituted Benzothiophenes: Synthesis, Mechanism, and Kinetic Studies

Article abstract of DOI:10.1002/hlca.201500285

The kinetics of the reaction of 4-methoxythiophenoxyacetaldehyde diethyl acetal, 4-nitrothiophenoxyacetaldehyde diethyl acetal, and 3-methoxythiophenoxyacetaldehyde diethyl acetal in polyphosphoric acid has been explained. The kinetic behavior has been ex

Full text of DOI:10.1002/hlca.201500285

384
Helv. Chim. Acta 2016, 99, 384 – 392
FULL PAPER
5
-Substituted Benzothiophenes: Synthesis, Mechanism, and Kinetic Studies
a
by Iole Cerminara ), Luciano D’Alessio ), Maurizio D’Auria* ), Maria Funicello ), and Ambra Guarnaccio )
a
a
a
b
a
)
Dipartimento di Scienze, Universit ꢀa della Basilicata, Viale dell’Ateneo Lucano 10, IT-85100 Potenza
phone: +39-0971-2054780, fax: +39-0971-205678, e-mail: maurizio.dauria@unibas.it)
(
b
)
Istituto di Struttura della Materia, U.O.S. Potenza, Consiglio Nazionale delle Ricerche, Zona Industriale, IT-85100 Tito
Scalo, Potenza
The kinetics of the reaction of 4-methoxythiophenoxyacetaldehyde diethyl acetal, 4-nitrothiophenoxyacetaldehyde
diethyl acetal, and 3-methoxythiophenoxyacetaldehyde diethyl acetal in polyphosphoric acid has been explained. The kinetic
behavior has been explained on the basis of aided simulation and on the basis of density functional theory calculations
showing a different pathway for 4-nitrothiophenoxyacetaldehyde diethyl acetal and for 4-methoxythiophenoxyacetaldehyde
diethyl acetal. In this last case, a very fast competing reaction to the dimerization product was observed.
Keywords: 5-Substituted benzothiophenes, Synthesis, Kinetics, DFT Calculations, Mathematical simulation.
using transition metals for the construction of the ben-
zothiophene skeleton, which would provide a more effi-
cient and practical route, are extremely rare in literature,
Introduction
Heteroarenes are widely known in many fields of organic
chemistry; in particular, medicinal chemistry is intimately presumably due to catalyst poisoning by sulfur. Only few
associated with heterocyclic compounds and most known recent reports are known [5] and the described methodol-
chemicals used in medicine are based on heterocyclic
frameworks [1].
There are two main sources of heteroarenes: they are
ogy is not applicable to the synthesis of all the substituted
benzothiophenes.
Moreover, mechanistic aspects in heterocyclic ring for-
abundance in nature, often in complex form; and they can mation are still of large interest in scientific community.
also be prepared in research laboratories by different syn- In this paper, we will discuss synthetic and mechanistic
thetic approaches. Here, we focus on the benzothiophene
Fig. 1) nucleus that shows a wide spectrum of biological
aspects, in particular, about the 5-substituted benzothio-
phene due to its importance for many biological active
compounds, for example, raloxifene [6] (Fig. 2) which is
an oral selective estrogen receptor modulator that has
estrogenic actions on bone and antiestrogenic actions on
the uterus and breast.
(
activities [2] as well as useful properties in material
science [3]. Thus, the development of efficient and selec-
tive methodologies for the construction of diversely func-
tionalized benzothiophenes is of considerable importance
in organic chemistry.
Furthermore, it is important to analyze the reaction
from a kinetic point of view with the aim to predict its
A large number of methods to synthesize heterocycles
containing benzothiophene ring have been reported in possible applicability on a large scale.
recent years [4], most of which involve the cyclization of
benzenethiol derivatives. However, facile and versatile
methods to access multisubstituted benzothiophenes are
still limited. Furthermore, catalytic cyclization approaches
Fig. 1. Benzothiophene derivatives.
Fig. 2. Raloxifene.
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2016 Verlag Helvetica Chimica Acta AG, Z u€ rich
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Helv. Chim. Acta 2016, 99, 384 – 392
385
Scheme 1. Synthesis of 5-substituted benzothiophenes.
Results and Discussion
Synthetic Aspects/Studies
In our long research in heterocyclic chemistry [7], we are
interested in obtaining 4- and 5-substituted heteroarenes
as suitable precursors for compounds active either against
HIV protease [4] or against BACE-1 in Alzheimer disease
[
2b]. Furthermore, 4- and 5-aminobenzothiophenes, and
- and 5-hydroxybenzothiophenes have been revealed as
4
the most useful compounds in medicinal chemistry, but
their synthesis has still a discussed approach: actually,
cyclization starting from a suitable benzenethiol repre-
sents the best methodology, even if the total chemical
yields appear unsatisfactory.
In particular, we recently reported the application of
Smiles rearrangement for the synthesis of 4-aminoben-
zothiophene [8], starting from the 4-hydroxy precursor
easily obtained as just known [9]. With the aim to obtain
Fig. 3. Structures of intermediates and disulfide in the synthesis of
5-methoxybenzothiophene.
5
-hydroxy- and 5-aminobenzo[b]thiophene by Smiles rear-
it has not been possible to assign one of the two pro-
posed structures (it is assumed that it can be either one
or the other).
We operated with 4-methoxybenzenthiol and decided
to monitor the reaction by the GC/MS analysis (the visi-
ble species are reported in Fig. 2) with a sequence of
sampling in a period of about 2 h, with the aim to under-
stand the pathway; the obtained data are reported in
Fig. 4.
rangement, we first prepared 5-methoxybenzothiophene;
but during these studies, we noted a particular trend of
the reaction.
The used synthetic approach to prepare 5-substituted
benzo[b]thiophenes is based on a classical methodology
[10], and it is still widely applied [11], consists of two
steps as shown in Scheme 1.
In the first step, the nucleophilic substitution product
2a or 2b) is obtained starting from the p-substituted ben-
(
The same protocol was repeated to prepare 5-nitro-
benzothiophene 3b which is a known compound synthe-
sized by different methodologies; in particular, it was
easily obtained by ring-opening/ring-closing procedure
described in several papers by Dell’Erba et al. [12].
Also in this case, the reaction was followed by GC/
MS with a sequence of sampling at regular time intervals
in a period of about 4 h; the results are reported in
Fig. 5.
zenethiol (commercial and cheap) and bromoacetalde-
hyde diethyl acetal under basic conditions.
This step proceeds with an excellent yield without
any formation of byproducts (2a 86% yield; 2b 99%
yield), but the second step represents an important
downfall of yields; in fact, we obtained only 48% for 3a
and 35% for 3b, respectively. This reaction consists of a
cyclization and aromatization process, typically con-
ducted with polyphosphoric acid in toluene, as well-
known in literature just from 1935 [10]. During our
attempts to obtain 3a, we detected the formation of dif-
ferent intermediate species including non-aromatic com-
pounds (4a and 5a, see Fig. 3) and a disulfide (6, see
Fig. 3) along with the desired 5-methoxybenzothiophene,
so we began to understand a possible mechanism and
decided to explore the potential electronic effect of the
From the MS data, it is possible to emphasize the for-
mation of four main compounds and the evolution
appears clear; compound 2b rapidly decreases to trans-
form first to compound 4b with m/z 225 and subsequently
to compound 5b with m/z 197 (Fig. 6). At this moment,
two routes are possible and the kinetic studies confirm
that these are in competition; one gives the desired 3b,
1
while the second gives compound 7 with m/z 271. )
substituent group (MeO-, -NO ). It is noteworthy that
2
all the discussed intermediates were not isolated, in par-
ticular, for the compounds 4a and 5a reported in Fig. 3,
1
) As regards intermediate 7, despite having the same m/z of compound 2b, its
fragmentation and retention time are different.
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386
Helv. Chim. Acta 2016, 99, 384 – 392
Fig. 4. Kinetics of the reaction 2a ? 3a.
Figure 5. Kinetics of the reaction 2b ? 3b.
Also in this case, with regard to intermediates 4b although it is clear that, in this case, two cyclization
and 5b, in Fig. 6 we reported the two possible struc-
tures.
products, 4- and 6-methoxybenzothiophene (3c, 4c)
starting from 3-methoxybenzenethiol 1c, (Scheme 2)
Furthermore, we also examined the behavior of the were possible. Our idea was that, in this case, the disul-
2
reaction in the synthesis of 4-methoxybenzothiophene ) fide will be not present because the substituent on ben-
zenethiol precursor was in meta-position.
2
The reaction with the yields and the GC/MS data are
)
The synthesis of 4-methoxybenzothiophene in good yield is well-known (as
reported in: L. F. Fieser, R. G. Kennelly, J. Am. Chem. Soc. 1935, 57,
611 – 1616; R. P. Napier, H. A. Kaufman, P. R. Driscoll, L. A. Glick, C.
reported in Scheme 2 and Fig. 7: it appears immediately
that the absence of the disulfide byproduct confirming the
hypothesis of a relevant electronic effect on the course of
cyclization; no other intermediates were visible to GC/
MS.
1
Chu, H. M. Foster, J. Heterocycl. Chem. 1970, 7, 393 – 394; A. Bekaert O.
Provot, O. Rasolojaona, M. Alami, J. -D. Brion, Tetrahedron Lett. 2005, 46,
4
2
1
187 – 4191; D. T. Drewry, R. M. Scrowston, J. Chem. Soc. C 1969,
750 – 2754; P. Dall, J. V. Johnson, C. E. Cook, J. Org. Chem. 1979, 44,
421 – 1424).
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Helv. Chim. Acta 2016, 99, 384 – 392
387
of the remarkable arithmetic and graphics capabilities of
this software.
The model equation has been coded in the Mathemat-
ica language and the solution was obtained by the
NDSolve numerical integrator of ordinary differential
equation. The code was performed in order to obtain a
graphical output. The values of the constant k . . . k are
1
5
continuously varied, in a suitable range, using the Manipu-
late dynamic function of the Mathematica notebook: five
sliders are defined, one for each constant, to set the numer-
ical values of the k’s and to see in real time the correspond-
ing integral curves superimposed to the experimental data:
an example of the output window is reported in Fig. 8.
With regard to the synthesis of 5-methoxybenzothio-
phene (3a), we have considered a kinetic model with the
branched-chain mechanism, i.e.,
sequence:
a
first-order linear
Fig. 6. Structures of the intermediates in the synthesis of 5-nitroben-
zothiophene.
A ! B ! C ! D
followed by a second-order dimerization side reaction:
Kinetic Studies
To test our hypotheses on the mechanism, we performed
some calculations on the kinetic results.
Although the above system can be solved analytically,
2C ! E
where A, B . . . E stand for the compounds whose m/z
values are 256 (2a), 210 (4a), 182 (5a), 164 (3a), and 278
we preferred to carry out a numerical integration with
Wolfram Mathematica 9 [13] in order to take advantage (6), respectively.
Scheme 2. Synthesis of 3c and 4c.
Fig. 7. Kinetics of the reaction 2c ? 3c + 4c.
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Helv. Chim. Acta 2016, 99, 384 – 392
In the synthesis of 5-nitrobenzothiophene (3b), we
used a kinetic model where the irreversible consecutive
first-order chemical reactions involving four species are
considered:
A ! B ! C ! D
followed by a side reaction:
B ! E
where A . . . E stand for the compounds whose m/z
values are 271 (2b), 225 (4b), 197 (5b), 179 (3b), and 271
(7a), respectively.
The time evolution of the model can be represented
by the following system of ordinary differential equations:
0
A ¼ ꢀk1A
0
B ¼ k1A ꢀ k2B ꢀ k4B
0
C ¼ k2B ꢀ k3C
0
D ¼ k3C
0
E ¼ k4B
0
0
where A . . . E are the time derivatives of the molar
concentration of the corresponding species A . . . E, and
k . . . k are the kinetic constants of the 1st . . . 4th reac-
Fig. 8. A screenshot of the Mathematica notebook with the experi-
mental (dots) and calculated (solid) kinetics.
1
5
tion of the chain.
Starting from the initial concentration of A at t = 0
in our case 0.1050M), the solution of the system gives the
(
evolution of the concentration of the six chemical species
as a function of time. Our problem is to match the theo-
retical values with the experimental ones in order to get
the best fit for the kinetic constants.
The time evolution of the model can be represented
by the following system of nonlinear first-order differen-
tial equations:
0
A ¼ ꢀk1A
The kinetic constants are then optimized by changing the
parameters until the computed curves match the data points.
The best fit is obtained by visual inspection. The obtained
0
B ¼ k1A ꢀ k2B
0
2
C ¼ k2B ꢀ k3C ꢀ k4C
ꢀ3
ꢀ5
ꢀ4
kinetic constants were k = 1.01 9 10 /s, k = 1.75 9 10
/
1
2
0
ꢀ
4
D ¼ k3C
s, k = 7.0 9 10 /s, and k = 2.5 9 10 /s.
3
4
0
2
E ¼ k4C
The order of magnitude of the results has been con-
firmed by a Monte Carlo optimization of the kinetic con-
0
0
0
where A , B . . . E are the time derivatives of the molar stants. We tried up to a million of different random
concentration of the corresponding species A, B. . . E, and values for the rate constants, and we have minimized the
k . . . k are the kinetic constants of the 1st. . . 4th reaction sum of the squared differences between the experimental
1
4
of the chain.
The initial concentration at t = 0 were 0.092M for A and
concentrations and those estimated by the model. The
results, calculated by Mathematica Wolfram, show a rea-
sonable agreement with the values previously obtained.
zero for the remaining species, in agreement with the
experimental setup. The computer simulation of the model
was carried out with the Mathematica software, and the
kinetic constants were optimized accordingly. The obtained
Mechanistic Studies/Aspects
ꢀ
4
values were the following: k = 9.53 9 10 /s, k = 1.38 9
On the basis of kinetic results, the following mechanism
can be proposed (Scheme 3). The proposed mechanism
1
2
ꢀ3
ꢀ4
ꢀ2
1
0
/s, k = 7.83 9 10 /s, and k = 2.77 9 10 /M s.
3
4
Scheme 3. Proposed reaction mechanism.
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Helv. Chim. Acta 2016, 99, 384 – 392
389
Fig. 9. Relative energy of some intermediates and transition states in the reaction 2a ? 3a. In the brackets, the negative frequency in the calcu-
lated infrared spectra.
consists of an electrophilic aromatic substitution induced
by the electrophiles (8a – b), followed by an aromatiza-
tion step due to the loss of EtOH.
To test this mechanism, we performed some density
functional theory (DFT) calculations at B3LYP/6-
Electrophilic aromatic substitution occurred on a sub-
strate where the thioether function directs the reaction on
the ortho-positions. These positions are in meta consider-
ing the MeO group. The substituents did not direct the
reaction in the same position. On the contrary, when the
3
the protonated form of compound 2a, it can lose EtOH
11G++(2d,p) level on Gaussian 09 [14]. Starting from reaction is performed on 2b, the activating thioether and
the deactivating nitro group directed the reaction on the
to give 8a (Scheme 3). The following step is an elec- same positions on the aromatic ring. In this case, the cal-
trophilic aromatic substitution reaction with activation culated transition state was 14.2 kcal/mol in agreement
energy of 16.1 kcal/mol to give the transition state ST2 with the higher reactivity of this substrate in comparison
and, then, the cyclized product (Fig. 9). It is noteworthy with 2a.
that 8a can undergo an elimination reaction to give ethyl
vinyl ether and the thiol. In this case, the reaction
occurred with a transition state (ST3) with energy of
38.9 kcal/mol. This is in agreement with the observed
kinetic behavior.
In this case, a description of the reactivity on the basis
of the interaction between HOMO and LUMO of the
reagents is not sufficient to describe the system. In
Fig. 10, we reported the HOMO and LUMO of 8a and
8b. The HOMO is mainly localized in the aromatic part
Fig. 10. HOMO and LUMO in 8a (left) and 8b (right).
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2016 Verlag Helvetica Chimica Acta AG, Z u€ rich
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390
Helv. Chim. Acta 2016, 99, 384 – 392
of the molecule, while the LUMO is mainly localized on
the cationic side chain. The energy difference between
HOMO and LUMO increased in 8b in contrast with the
experimental results. We can suppose, in this case, that
Experimental Part
General
the role of polar component in Klopman–Salem equa- CH
Cl
was dried by distillation over anh. CaCl
inert atmosphere; Et O and THF were dried using Na/
in an
2
2
2
tion [15] is relevant if compared with the role of frontier
orbitals.
2
benzophenone. Dry DMF, toluene, and chlorobenzene
were commercially available. Thin-layer chromatography
(TLC) was carried out on precoated silica gel 60 plates
Conclusions
(0.2 mm thickness) with the indicated solvents, and the
plates were scanned under ultraviolet light at 254 and
The reaction of 4-methoxythiophenoxyacetaldehyde
diethyl acetal, 4-nitrothiophenoxyacetaldehyde diethyl
acetal, and 3-methoxythiophenoxyacetaldehyde diethyl
acetal in polyphosphoric acid showed a complex kinetic
behavior. Both computer-aided kinetic simulation and
DFT calculations allowed to explain the observed behav-
ior. In particular, the electronic effect of the substituent
groups seems crucial in directing the cyclization and
aromatization step. As suggested by the analysis of the
experimental data and as confirmed by calculations,
methoxy-substituted and nitro-substituted derivatives fol-
low different reaction paths which are directed by acti-
vating/deactivating nature of these groups and their
relative position to the thioether function in the interme-
diates 8a and 8b. Moreover, these effects influence the
conversion of the intermediates into the final main
products, i.e., the disulfide 6 starting from 4-methoxy-
thiophenoxyacetaldehyde diethyl acetal and 5-nitroben-
zothiophene 3b, starting from 4-nitrothiophenoxyacetald-
ehyde diethyl acetal.
3
65 nm. Column chromatography was carried out on Mer-
ck (Darmstadt, Gemany) silica gel 60 (70 – 230 mesh
ASTM). Petroleum ether (PE) refers to the boiling range
40 – 60°. When a solvent gradient was used, the increase
in polarity was done gradually from PE to mixtures of
Et O/PE or AcOEt/PE. All the intermediates were not
2
isolated but exclusively analyzed by GC/MS so their char-
acterization is not reported. M.p.: Mell-Temp-II apparatus
1
Sigma-Aldrich. Milan, Italy); uncorrected. H- and C-
13
(
NMR spectra: Varian INOVA 400 and 500 MHz instru-
ments (Palo Alto, California, USA), in CDCl3 soln. at
room temperature with TMS as an internal reference; the
chemical shifts are reported in ppm of TMS in d units,
and the J values are given in Hertz (Hz). MS: Hewlett–
Packard GC/MS 6890-5973 (Agilent, Santa Clara, Califor-
nia, USA).
1
-[(2,2-Diethoxyethyl)sulfanyl]-4-methoxybenzene (2a). In
a reaction flask, in an inert atmosphere, commercial 4-
methoxybenzenethiol (1a) (2.31 g, 16.5 mmol) was dis-
solved in anhydrous DMF, then potassium carbonate
In 3-methoxythiophenoxyacetaldehyde diethyl acetal,
disulfide formation is not observed confirming the impor-
tance of substituent position relative to the intermediate:
in this case, in fact, the thioether function and the MeO
group lead the reaction in the same direction (on the
ortho-para positions with prevalence of 4c product forma-
tion).
(
(
5.01 g, 36.3 mmol) and bromoacetaldehyde diethyl acetal
= 2-bromo-1,1-diethoxyethane; 3.4 ml, 19.8 mmol) were
added and the mixture was brought to reflux (153°). Dur-
ing the heating phase, the following color changes were
observed: the mixture turned from milky white to pale
yellow; and after 6 h of reflux, when the reaction was
stopped, the mixture appeared brown and clear.
In summary, in this work, starting from the experi-
mental kinetic data in agreement with computer simula-
tions and DFT calculations, a hypothesis about the
mechanism in the synthesis of 5-substituted benzothio-
phenes from the corresponding thiophenoxyacetaldehyde
diethyl acetals has been formulated.
The quench involved about 100 ml of distilled water
and three extractions with Et O. The organic layers were
2
washed with a saturated solution of NH Cl, water, brine,
4
finally dried over anhydrous Na SO , and concentrated
2
4
under reduced pressure. The dark red oil obtained was
purified by chromatographic column packed with silica
and eluted with hexane/Et O (9:1), giving 3.63 g (yield
In particular, in 4-nitrothiophenoxyacetaldehyde
diethyl acetal, the rate determining step was
2
8
hexane/Et O 9:1).
6%) of pure product (2a) (yellow thick oil; R 0.4 with
f
ꢀ4
k2 = 1.75 9 10 /s, corresponding to an electrophilic reac-
tion. In the case of 4-methoxythiophenoxyacetaldehyde
diethyl acetal, the rate determining step was
1
H-NMR (400 MHz, CDCl3):
2
1
2
6
.21 – 1.18 (t, 6 H); 3.04 – 3.02 (m, 2 H); 3.53 – 3.51 (m,
H); 3.79 – 3.54 (m, 2 H); 3.80 (s, 3 H); 4.60 (t, 1 H);
ꢀ4
k3 = 7.83 9 10 /s, corresponding to the same type of
reaction. Furthermore, in this work for the first time, the
application of the Wolfram Mathematica 9 to the kinetic
parameters estimation of a complex chemical system is
described.
13
.85 – 6.83 (d, 2 H); 7.40 – 7.38 (d, 2 H). C-NMR
(
125 MHz, CDCl ): d = 15.21; 55.90; 61.06; 66.02; 102.69;
3
1
14.23; 114.56; 127.54; 127.98; 128.13; 157.10 ppm. MS
+
(
EI, 70 eV): 256 (27) [M ], 165 (22), 139 (44), 103 (100),
5 (52), 47 (31).
-Benzothiophen-5-yl Methyl Ether (3a). To a reaction
flask containing the polyphosphoric acid (2.58 g,
7
1
We gratefully acknowledge the University of Basilicata
for their financial support.
1
1.34 mmol) in anhydrous toluene (70 ml), 1-[(2,2-
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Helv. Chim. Acta 2016, 99, 384 – 392
391
diethoxyethyl)sulfanyl]-4-methoxybenzene (2a) (2.42 g, After this time, a check on TLC (9:1 hexane/Et O)
2
9
1
.45 mmol) was added and the mixture is refluxed for
7 h in an inert atmosphere. After this time, a check on
showed the disappearance of the substrate, so the reaction
was stopped. For the quench, a solution of 4M KOH was
TLC (8:2 hexane/Et O) showed the disappearance of the added dropwise to the reaction mixture until neutrality.
2
substrate, so the reaction was stopped. For the quench, a
solution of 4M KOH was added dropwise to the reaction
mixture until neutrality. Extractions with Et O provided and concentrated under reduced pressure. The crude oil
Extractions with Et O provided the organic phases that
2
were washed with brine, dried over anhydrous Na SO ,
2
4
2
the organic phases that were washed with brine, dried
was purified on chromatographic column packed with sil-
over anhydrous Na SO , and concentrated under reduced ica and eluted with hexane/CH Cl (7:3), to afford 47 mg
2
4
2
2
pressure. The crude dense and dark red oil was purified
on chromatographic column packed with silica and eluted
with hexane/Et O (8:2), to afford 372 mg (yield 24%) of
(yield 15%) of 1-benzothiophen-4-yl methyl ether (3c)
(thick yellow oil; R 0.7 with hexane/CH Cl 7:3) and
203 mg (yield 65%) of 1-benzothiophen-6-yl methyl ether
f
2
2
2
1
-benzothiophen-5-yl methyl ether (3a) (thick fragrant (4c) (thick fragrant yellow oil; R 0.4 with hexane/CH Cl
f 2 2
1
yellow oil; R 0.7 with hexane/Et O (8:2) and 744 mg
7:3). Data of 1-benzothiophen-4-yl methyl ether (3c): H-
NMR (500 MHz, CDCl3): 3.98 (s, H); 6.77 (d,
yellow oil; R 0.4 with hexane/Et O 8:2). Data of 1-ben- J = 7.2 Hz, 1 H); 7.31 (d, J = 7.5 Hz, 1 H); 7.35 (dd,
f
2
(
yield 48%) of bis(4-methoxyphenyl) disulfide (6a) (thick
3
f
2
1
zothiophen-5-yl methyl ether (3a): M.p.: 44 – 45°. H- J = 6.5 Hz,
NMR (500 MHz, CDCl ): 3.81 (s, 3 H); 6.93 (d, J = 5 Hz, (d, J = 5 Hz, 1 H). C-NMR (100 MHz, CDCl ): 55.39;
1 H); 7.48 (d, J = 7.5 Hz, 1 H); 7.52
1
3
3
3
1
H); 7.22 – 7.20 (m, 2 H); 7.37 (d, J = 5 Hz, 1 H); 7.67 103.75; 114.82; 120.51; 124.57; 125.24; 130.42; 141.29;
1
3
+
(d, J = 10 Hz, 1 H). C-NMR (125 MHz, CDCl ): 55.5; 155.04. MS (EI, 70 eV): 164 (100) [M ], 149 (95), 121(65),
3
1
05.5; 114.6; 123.1; 123.6; 127.5; 132.1; 140.6; 157.4. MS
77 (14). Data of 1-benzothiophen-6-yl methyl ether (4c):
1
+
EI, 70 eV): 164 (100) [M ], 149 (64), 121 (62). Bis(4-
(
methoxyphenyl) disulfide (6a): H-NMR (400 MHz,
H-NMR (500 MHz, CDCl ): 3.90 (s, 3 H); 7.06 (dd,
3
1
J = 9 Hz, 1 H); 7.28 (m, 2 H); 7.38 (d, J = 2 Hz, 1 H);
1
3
CDCl ): 3.76 (s, 3 H); 6.83 – 6.85 (m, 4 H); 7.42 – 7.44 7.73 (dd, J = 8.5 Hz, 1 H). C-NMR (100 MHz, CDCl3):
3
1
3
m, 4 H). C-NMR (125 MHz, CDCl ): 55.1; 114.4; 128.1; 55.50; 104.74; 114.35; 123.34; 123.61; 124.04; 133.60;
(
3
+
32.4; 159.7. MS (EI, 70 eV): 278 (56) [M ], 139 (100).
-[(2,2-Diethoxyethyl)sulfanyl]-3-methoxybenzene (2c). In 1-[(2,2-Diethoxyethyl)sulfanyl]-4-nitrobenzene (2b). In a
+
141.13; 157.33. MS (EI, 70 eV): 164 [M ].
1
1
a reaction flask, in an inert atmosphere, commercial 3-
methoxybenzenethiol (1c) (400 mg, 2.85 mmol) was dis-
solved in anhydrous DMF, then potassium carbonate
reaction flask, in an inert atmosphere, commercial 4-nitro-
benzenethiol (1b) (1.10 g, 7.1 mmol) was dissolved in
anhydrous DMF, then potassium carbonate (2.36 g,
17.1 mmol) and bromoacetaldehyde diethyl acetal
(1.4 ml, 9.3 mmol) were added, and the mixture was
refluxed for 2 h. During the heating phase, the mixture
turned from yellow to red. The quench was conducted
(
3
860 mg, 6.22 mmol) and diethyl bromoacetal (0.5 ml,
.38 mmol) were added, and the mixture was refluxed.
During the heating phase, the following color changes
were observed: after 15 min, the mixture turned from
white to yellow; and after 1 h of reflux, the mixture
appeared brown/greenish. After 150 min, the reaction was
stopped, treated with distilled water and extracted with
with about 200 ml of distilled H O and three extractions
2
with AcOEt. The organic layers were washed with a satu-
rated solution of NH Cl, water, brine, finally dried over
4
Et O. The organic layers were washed with a saturated
2
anhydrous Na SO , and concentrated under reduced pres-
2
4
solution of NH Cl, water, brine, finally dried over anhy-
sure. The dark red oil obtained was purified by chromato-
drous Na SO , and concentrated under reduced pressure. graphic column packed with silica and eluted with
4
2
4
The dark oil obtained was purified by chromatographic
column packed with silica and eluted with hexane/Et O duct (2b) (yellow thick oil; R 0.3 with hexane/Et O 8: 2).
hexane/Et O (8:2), giving 1.88 g (yield 99%) of pure pro-
2
2
f
2
1
(
(
8:2), giving 485 mg (yield 67%) of pure product (2c)
1
H-NMR (500 MHz, CDCl3): 1.19 – 1.16 (t, 6 H);
colorless thick oil; R 0.4 with 9:1 hexane/Et O). H- 3.22 – 3.20 (d, 2 H); 3.57 – 3.53 (q, 2 H); 3.70 – 368 (q, 2
f
2
NMR (400 MHz, CDCl ): 1.20 (t, J = 7.2 Hz, 6 H); 3.14 H); 4.68 (t, 1 H); 7.40 – 7.37 (d, 2 H); 8.07 – 8.06 (d, 2
3
1
3
(
d, J = 5.6 Hz, 2 H); 3.53 – 3.57 (m, 2 H); 3.66 – 3.79 (m, H). C-NMR (125 MHz, CDCl ): 15.12; 35.76; 62.64;
3
2
H); 3.80 (s, 3 H); 4.66 (t, J = 5.6 Hz, 1 H); 6.72 (dd, 101.46; 123.69; 126.45; 145.02; 147.28. MS (EI, 70 eV): 271
+
J = 8.2 Hz, 1 H); 6.94 (m, 2 H); 7.19 (t, J = 8.0 Hz, 1 H). [M ], 226 (13), 103 (100), 75 (49), 47 (42).
C-NMR (100 MHz, CDCl ): 15.2; 37.3; 55.3; 62.2; 101.7; 5-Nitro-1-benzothiophene (3b). To a reaction flask con-
13
3
1
2
11.8; 114.3; 121.3; 129.6; 137.9; 159.8. MS (EI, 70 eV):
56 [M ].
taining the polyphosphoric acid (6.38 g, 28 mmol) in
anhydrous toluene (65 ml), 1-[(2,2-diethoxyethyl)sulfa-
-Benzothiophen-4-yl methyl ether (3c) and 1-Benzothio- nyl]-4-nitrobenzene (2b) (1.88 g, 6.94 mmol) was added
+
1
phen-6-yl methyl ether (4c). To a reaction flask containing and the mixture was refluxed for 4 h in an inert atmo-
the polyphosphoric acid (508 mg, 2.22 mmol), 1-[(2,2- sphere. After this time, a check on TLC (9:1 hexane/
diethoxyethyl)sulfanyl]-3-methoxybenzene (2c) (485 mg, Et O) showed the disappearance of the substrate, so the
2
1.89 mmol) was added in anhydrous toluene (20 ml) and
the mixture was refluxed for 3 h in an inert atmosphere.
reaction was stopped. For the quench, a solution of 4M
KOH was added dropwise to the reaction mixture until
©
2016 Verlag Helvetica Chimica Acta AG, Z u€ rich
www.helv.wiley.com

392
Helv. Chim. Acta 2016, 99, 384 – 392
neutrality. The mixture was extracted with Et O and
2
Commun. 2008, 5529; C. W. Cheung, D. S. Surry, S. L. Buch-
wald, Org. Lett. 2013, 15, 3734; C. W. Cheung, S. L. Buchwald,
Org. Lett. 2013, 15, 3998.
washed with brine. The combined organic extracts were
dried with Na SO and concentrated under vacuum. The
2
4
[
[
6] A. D. Palkowitz, A. L. Glasebrok, K. J. Thrasher, K. L. Hauser,
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crude dense and dark brown oil was purified on chro-
matographic column packed with silica and eluted with
hexanes/Et O (9:1), to afford 434 mg (yield 35%) of 5-
2
nitro-1-benzothiophene (3b) (yellow solid; Rf 0.5 with
1
hexane/Et O 9:1). M.p.: 135 – 137°. H-NMR (400 MHz.
2
7] M. Funicello, P. Spagnolo, in ‘Targets in Heterocyclic Chem-
istry’, Vol. 8, Eds. O. A. Attanasi and D. Spinelli, Royal Society
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CDCl ): 7.41 – 7.40 (d, 1 H); 7.57 – 7.56 (d, 1 H);
3
7
.89 – 7.87 (d, 1 H); 8.10 – 8.08 (d, 1 H); 8.61 (s, 1 H).
C-NMR (100 MHz, CDCl ): 118.48; 119.22; 122.93;
1
3
3
1
24.64; 129.95; 131.05; 139.24; 145.47. MS (EI, 70 eV): 179
+
100) [M ], 149 (11), 133 (71), 121 (22), 89 (51).
(
Theoretical Calculations
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003, 59, 7515.
2
All the calculations were performed by using the Gaus-
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the Becke’s three-parameter hybrid exchange-correlation
functional known as B3LYP [17]. The 6-31+G(d,p) basis
set was applied for all the calculations as implemented in
the Gaussian 09 program. All the optimized geometries
were obtained by using the standard thresholds for self-
consistent field computations and geometry optimizations.
Analytical evaluation of the energy second derivative
matrix (Hessian matrix) with respect to Cartesian coordi-
nates at the same level of approximation confirmed the
nature of minima and transition structures of the energy
surface points associated to the optimized structures. All
the computations have been performed by using the
Gaussian 09 standard approach which considers the mole-
cule in vacuum.
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Received November 9, 2015
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© 2016 Verlag Helvetica Chimica Acta AG, Z u€ rich