Use of Phenacyl Thiosalicylates for the Preparation of 3-Hydroxybenzo[ b ]thiophene Derivatives

Article abstract of DOI:10.1055/s-0036-1591875

In this work, we attempted to synthesize thioflavonols using rearrangement of phenacyl thiosalicylates prepared by two different approaches and subjected to cyclization under acidic conditions. Contrary to our expectations, the isolated products were iden

Full text of DOI:10.1055/s-0036-1591875

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
letter
A
en
P. Trapani et al.
Letter
Synlett
Use of Phenacyl Thiosalicylates for the Preparation of 3-Hydroxy-
benzo[b]thiophene Derivatives
Patricia Trapania
Lubomír Kvapila
Pavel Hradila
Miroslav Soural*b
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7-
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8-
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a Department of Organic Chemistry, Faculty of Science, Palacký
University, 17. Listopadu 12, 771 46 Olomouc, Czech Republic
b Institute of Molecular and Translation Medicine, Faculty of
Medicine and Dentistry, Palacký University, Hněvotínská 5,
779 00, Olomouc, Czech Republic
Miroslav.soural@upol.cz
Received: 03.10.2017
Accepted after revision: 27.11.2017
Published online: 06.02.2018
yloxy)thiochromen-4-one15 and an unexpected rearrange-
ment of thioaurones using triethylsilane under the solid-
phase-synthesis conditions was described by Varedian et
al.16 Taking the limitation of all of the reported methods in
account, the cyclization of phenacyl thiosalicylates was ex-
pected to be potentially the most beneficial method. The
actual reaction outcome and mechanistic study of the un-
expected products are summarized in this article.
DOI: 10.1055/s-0036-1591875; Art ID: st-2017-d0732-l
Abstract In this work, we attempted to synthesize thioflavonols using
rearrangement of phenacyl thiosalicylates prepared by two different
approaches and subjected to cyclization under acidic conditions. Con-
trary to our expectations, the isolated products were identified as (3-
hydroxybenzo[b]thiophen-2-yl)(phenyl)methanones. The detailed reac-
tion mechanism was elucidated by characterization of all reaction inter-
mediates with HPLC and NMR spectroscopy. The applicability of the re-
action using different phenacyl esters was tested.
The preparation of phenacyl thiosalicylates 6 has not
been previously reported, and, for this reason, two alterna-
tive methods using readily available starting materials were
developed. In the first approach thiosalicylic acid (1) was
converted into S-acetyl derivative 2, which was alkylated
with 2-bromo-1-phenylethan-1-one, and the resulting
intermediate 3a was deacetylated using aqueous ammo-
nia.17 Alternatively, 2,2′-disulfanediyldibenzoic acid (4) was
alkylated with 2-bromo-1-(4-methoxyphenyl)ethan-1-one,
and the resulting bisphenacyl ester 5b was reduced with
triphenylphosphine (Scheme 2).18 To test the acid-mediated
cyclization, we chose trifluoroacetic acid (TFA) as a suitable
reagent that had been previously used for simple conver-
sion of phenacyl anthranilates into the corresponding
hydroxyquinolinones.19 After heating at reflux for several
hours, the major product was isolated and characterized.20
Although the mass spectrometry and elemental analysis
data corresponded to the values calculated for the desired
thioflavonol, after careful investigation of the NMR data a
different structural outcome was suggested (derivatives
7a,b, see Scheme 3).
Key words rearrangement, heterocycles, benzo[b]thiophene, thio-
salicylates, bromoketones
Phenacyl esters of anthranilic acid derivatives have been
reported as excellent starting materials for the straight-
forward synthesis of flavonol analogues.1 Most frequently,
their rearrangement under acidic conditions was used to
readily obtain 3-hydroxyquinolin-4(1H)-ones2 I as com-
pounds with interesting biological3–6 and fluorescent6–10
properties. The same course of reaction was observed with
phenacyl thioanthranilates and resulted in the formation of
3-sulfanylquinolin-4(1H)-ones II and the corresponding di-
sulfides.11 When the phenacylamides of anthranilic acid
were subjected to acid-mediated cyclization, 3-aminoquino-
lin-4(1H)-ones III were obtained.12 Finally, analogous be-
havior was recently described for phenacylamides of anilin-
2-sulfonic acid to yield the benzothiazine-1,1-dioxides IV
(Scheme 1).13
Inspired by these reports, we considered an application
of the rearrangement to access thioflavonols V. In the litera-
ture, the preparation of such compounds has been reported
very rarely. The first contribution was published by Eistert
and Selzer using benzo[b]thiophene-2,3-dione as the start-
ing material.14 Majumdar and Roy developed a thermal
[3,3]-sigmatropic rearrangement of 3-(2-cyclohexen-1-
A literature survey revealed that benzothiophene 7a
had been previously synthesized by the cyclization of S-
phenacyl thiosalicylic acid (8a), and the structure of the
product was unambiguously elucidated by X-ray analysis.21
To prove the suggested structure of our product, compound
8a was synthesized according to the published procedure21
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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P. Trapani et al.
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Synlett
O
OH
N
H
I
X = CO
Y = O
Z = NH2
X = CO
Y = NH
Z = NH2
X = CO
Y = S
Z = NH2
O
O
SH
NH2
X
Z
Y
O
N
H
N
H
III
II
X = SO2
Y = NR
Z = NH2
X = CO
Y = O
Z = SH
O
O2
S
H
N
R
OH
?
N
H
S
V
IV
Scheme 1 Use of the phenacyl derivatives for the preparation of diverse analogues of flavonols
and subjected to the reaction in TFA (Scheme 4). Compari-
son of the individual NMR spectra proved that the cycliza-
tion of the intermediates 6a and 8a yielded an identical
product. Furthermore, all physical and spectroscopic prop-
erties of 7a were in accordance with the previously pub-
lished data.21
R
O
S
COOH
S
COOH
SH
(iv)
(iii)
O
O
2
3a
O
O
1
(v)
R
TFA
reflux
3.5 h
OH
O
O
O
R
COOH
OH
O
O
S
O
O
(ii)
(i)
S
S
S
O
S
S
O
O
SH
8a
7a
6a,b
O
Scheme 4 Preparation of compound 7a from sulfide 8a
COOH
R
a: R = H
b: R = 4-OMe
O
5b
4
Scheme 2 Synthesis of phenacyl thiosalicylates. Reagents and condi-
tions: (i) 2-bromo-1-(4-methoxyphenyl)ethan-1-one, DIPEA, DMF, rt,
16 h; (ii) PPh3, 2-mercaptoethanol, water, degassed THF, 50 °C, 16 h;
(iii) AcOH, AcCl, reflux, 1 h; (iv) 2-bromo-1-phenylethan-1-one, triethyl-
amine (TEA), N,N-dimethylformamide (DMF), rt, 4 h; (v) N-methylpyrro-
lidone (NMP), NH4OH, rt, 10 min.
In contrast to the previously reported conversion of 8a
into 7a, formation of derivatives 7 from esters 6 was sur-
prising and for this reason, it was further investigated.
When the compound 6a was heated under reflux in TFA for
only 1 h, the starting material disappeared and, beside the
final product 7a, the reaction intermediates were detected
using LC–UV–MS analysis. The molecular mass of the most
R
O
S
O
OH
TFA
reflux
TFA
reflux
OH
O
O
O
S
SH
R
7a,b
R
6a,b
a: R = H
b: R = 4-OMe
Scheme 3 Cyclization of phenacyl thiosalicylates using TFA
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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P. Trapani et al.
Letter
Synlett
H
O
S
O
O
O
H
OH
O
O
O
S
H
SH
H
O
8a
6a
Scheme 5 Reaction mechanism explaining formation of 8a
O
_
O
O
O
O
S
_
H
O
O
H
OH
O
O
O
_
O
H
+
O
SH
S
SH
H
O
6a
9a
O
SH
Scheme 6 Reaction mechanism explaining conversion of 6a into 9a
prevalent intermediate corresponded to the bisphenacyl
derivative 9a (Scheme 6). This compound was isolated and
its structure was confirmed by NMR spectroscopy. The sec-
ond detected intermediate was derivative 8a, which was
identified by comparison of its retention time, UV, and MS
spectra with the synthesized standard.21 Furthermore, thio-
salicylic acid was also detected. After heating for another
2.5 h, both of the intermediates 8a and 9a were almost
quantitatively converted into the product 7a. These findings
reveal the overall reaction mechanism depicted in Schemes
5–8. Heating the starting material 6a in acid leads to the fol-
lowing series of transformations: (i) compound 6a under-
goes intramolecular rearrangement to give intermediate 8a
(Scheme 5); (ii) formation of compound 9a from 6a takes
place via intermolecular alkylation which releases thiosali-
cylic acid (1, Scheme 6); (iii) under acidic catalysis, com-
pound 8a furnishes product 7a as reported previously
(Scheme 7);21 intermediate 9a undergoes a similar type of
conversion (Scheme 8). It is worth mentioning that the use
of acetic acid as a reagent provided similar results.
Further experiments proved that intermediate 3a fur-
nished the corresponding benzothiophene 7a directly by
heating in trifluoroacetic acid, indicating that the S-
deacetylation step can be avoided in the reaction sequence
(Scheme 9). To determine limitation and scope of the rear-
rangement, a set of different esters 3 was prepared and sub-
jected to TFA cyclization.
In case of 4-substituted compounds 3b–e, the reaction
yielded the target compounds 7 in good crude purity for
both electron-donating and electron-withdrawing substit-
uents (with exception of the 4-NO2 derivative, which gave
the desired product 7h as a part of complex mixture). Good
results were also obtained for naphthyl and thienyl deriva-
HO
OH
S
O
S
H
O
H
O
H
H
OH
H
S
O
O
O
8a
H
H
OH
HO
H
O
HO
O
OH
O
O
S
S
H
S
H3O
7a
Scheme 7 Reaction mechanism describing conversion of 8a into 7a
tives. In contrast, 2-phenyl-substituted intermediates 3h–j
yielded benzothiophenes 7h–j accompanied by a number of
unknown byproducts and, in these cases, the desired prod-
ucts were not isolated. In the case of tBu intermediate 3m,
the corresponding product 7m was not obtained at all. In
the reaction mixture, only the S-deacetylated intermediate
6m was detected by LC–MS after heating with TFA for 3 h.
Presumably, the rearrangement did not proceed due to ste-
ric hindrance. This indicates that the conversion of the in-
termediates 3 into 7 is generally started by deacetylation
leading to in situ formation of compounds 6 followed by the
set of transformations summarized in Schemes 5–8. Finally,
it was discovered that benzothiophene 7c can be quantita-
tively obtained by alkylation of compound 4 (Scheme 2,
step iv) at elevated temperature (80 °C). This shows that in-
termediate 5c is capable of rearranging directly to product
7c under both acidic and basic conditions. On the other
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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P. Trapani et al.
Letter
Synlett
predict the reactivity of similar systems. The straightfor-
ward and versatile approach for the synthesis of thioflavo-
nols remains the future goal of organic synthetic chemistry.
O
O
O
O
O
O
O
H
H
O
Funding Information
O
O
H
S
S
S
The authors are grateful to project CZ.1.07/2.3.00/20.0009 from the
European Social Fund and internal grants from Palacký University
(IGA_PrF_2017_009 and IGA_LF_2017_028). The infrastructure of this
project (Institute of Molecular and Translation Medicine) was sup-
O
H
OH
9a
ported by the National Program of Sustainability (project LO1304).
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Supporting Information
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O
O
HO
Supporting information contains details of experimental, synthetic
and analytical procedures along with spectroscopic data for synthe-
sized compounds.Supporting information for this article is available
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online at https://doi.org/10.1055/s-0036-1591875.
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References and Notes
Scheme 8 Plausible reaction mechanism describing conversion of 9a
into 7a
(1) Soural, M.; Hradil Křupková, S.; Hlaváč, J. Mini-Rev. Org. Chem.
2012, 9, 426.
(2) Hradil, P.; Jirman, J. Collect. Czech. Chem. Commun. 1995, 60,
1357.
(3) Hradil, P.; Hlaváč, J.; Soural, M.; Hajdúch, M.; Kolář, M.;
Večeřová, R. Mini-Rev. Med. Chem. 2009, 9, 696.
O
S
OH
TFA
reflux
R
O
R
O
O
S
(4) Soural, M.; Hlaváč, J.; Hradil, P.; Fryšová, I.; Hajdúch, M.;
Bertolasi, V.; Maloň, M. Eur. J. Med. Chem. 2006, 41, 467.
(5) Kubesova, K.; Doricakova, A.; Travnicek, Z.; Dvorak, Z. Toxicol.
Lett. 2016, 255, 24.
O
R
R
7a–e, k, l
3h 2-NO2C6H4
3a Ph
3i
3j
2-MeC6H4
2-BrC6H4
3b 4-MeOC6H4
3c 4-CF3C6H4
3d 4-MeC6H4
3e 4-BrC6H4
(6) Funk, P.; Motyka, K.; Džubák, P.; Znojek, P.; Gurská, S.; Kusz, J.;
McMaster, C.; Hajdúch, M.; Soural, M. RSC Adv. 2015, 5, 48861.
(7) Bilokin´, M. D.; Shvadchak, V. V.; Yushchenko, D. A.;
Klymchenko, A. S.; Duportail, G.; Mely, Y.; Pivovarenko, V. G.
Tetrahedron Lett. 2009, 50, 4714.
3k 3-thienyl
3l 2-napthyl
3m tBu
3f
4-NO2C6H4
3g 3-NO2C6H4
(8) Yushchenko, D. A.; Shvadchak, V. V.; Klymchenko, A. S.;
Duportail, G.; Mely, Y.; Pivovarenko, V. G. New J. Chem. 2006, 30,
774.
Scheme 9 Cyclization of S-acetyl intermediates
(9) Yushchenko, D. A.; Bilokin´, M. D.; Pyvovarenko, O. V.; Duportail,
G.; Mely, Y.; Pivovarenko, V. G. Tetrahedron Lett. 2006, 47, 905.
(10) Kadric, J.; Motyka, K.; Džubák, P.; Hajdúch, M.; Soural, M. Tetra-
hedron Lett. 2014, 55, 3592.
(11) Soural, M.; Hlavac, J.; Hradil, P.; Hajduch, M. Eur. J. Org. Chem.
2009, 3867.
hand, simultaneous alkylation and rearrangement using 2-
bromo-1-(4-methoxyphenyl)ethan-1-one and 2-bromo-1-
phenylethan-1-one at elevated temperature was very slow
and yielded the products 7a,b in low purities. Consequent-
ly, in contrast to acid-mediated reaction, the applicability of
base-catalyzed rearrangement is limited to electron-with-
drawing substituents.
In conclusion, rearrangement of phenacyl thiosalicy-
lates has been discovered as an alternative method for the
preparation of (3-hydroxybenzo[b]thiophen-2-yl)(phe-
nyl)methanones21,22 that have been currently reported as
potent agents against treatment-resistant breast cancer.23
The stability of the benzo[b]thiophene scaffold led to pref-
erential formation of such products and the presence of
thioflavonols was not detected. The reported reaction is in-
teresting from a mechanistic viewpoint and can be used to
(12) Hradil, P.; Grepl, M.; Hlavac, J.; Soural, M.; Malon, M.; Bertolasi,
V. J. Org. Chem. 2006, 71, 819.
(13) Fulopova, V.; Krchnak, V. J. Org. Chem. 2015, 80, 1795.
(14) Eistert, B.; Selzer, H. Chem. Ber. 1963, 96, 1234.
(15) Majumdar, K. C.; Roy, B. Synth. Comm. 2003, 33, 133.
(16) Varedian, M. V.; Langer, V.; Bergquist, J.; Gogoll, A. Tetrahedron
Lett. 2008, 49, 6033.
(17) Phenacyl ester 3a (2.5 g, 8 mmol) was dissolved in NMP (10 mL),
and aqueous ammonia (7.5 mL) was added dropwise. The tem-
perature spontaneously increased to 30 °C. After stirring for 10
min, the reaction mixture was diluted with water (50 mL) and
acidified with dil. hydrochloric acid to pH 1–2. The precipitated
solid was removed by suction, washed with water, and dried.
The crude product 6a was crystallized from 2-methoxyethanol
to give the product in a yield of 50%. 1H NMR (500 MHz, CDCl3):
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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δ = 8.22–8.16 (m, 1 H), 8.01–7.91 (m, 2 H), 7.66–7.59 (m, 1 H),
7.54–7.47 (m, 2 H), 7.38–7.30 (m, 2 H), 7.20 (m, 1 H), 5.59 (s, 2
H), 4.73 (s, 1 H) ppm.13C NMR (126 MHz, CDCl3): δ = 191.98,
166.20, 138.82, 134.31, 134.12, 132.98, 132.31, 131.00, 129.06,
127.97, 125.34, 124.92, 66.65 ppm. HRMS (ESI-TOF): m/z calcd
for C15H12O3S [M – H]–: 271.0433; found: 271.0435.
evaporated under a stream of nitrogen, and the yellow oily
residue was purified by semipreparative HPLC to obtain the cor-
responding benzothiophene.
1
Compound 7a: yield 80%. H NMR (500 MHz, CDCl3): δ = 13.45
(s, 1 H), 8.10–8.01 (m, 3 H), 7.74 (d, J = 8.2 Hz, 1 H), 7.65–7.59
(m, 1 H), 7.58–7.51 (m, 3 H), 7.44 (t, J = 7.5 Hz, 1 H) ppm.13
C
(18) Bisphenacyl ester 5b (681 mg, 1.3 mmol) was dissolved in
degassed THF (10 mL), then PPh3(511 mg, 1.95 mmol), 2-mer-
captoethanol (95 μL, 1.3 mmol), and water (235 μL) were added.
The reaction mixture was then stirred at 50 °C for 24 h. After
completion of the reaction, the THF was evaporated, the yellow
oily residue was diluted with brine (100 mL) and then extracted
with DCM (3 × 90 mL). The combined organic layers were dried
over Na2SO4, filtered, and evaporated. The oily residue was puri-
fied by column chromatography (SiO2, hexane/EtOAc = 2:1) to
obtain pure phenacyl ester 6b in a yield of 35%. 1H NMR (500
MHz, CDCl3): δ = 8.22–8.15 (m, 1 H), 7.99–7.89 (m, 2 H), 7.36–
7.31 (m, 2 H), 7.23–7.16 (m, 1 H), 7.00–6.91 (m, 2 H), 5.58–5.50
(s, 2 H), 4.75 (s, 1 H), 3.88 (s, 3 H) ppm. 13C NMR (126 MHz,
CDCl3): δ = 190.43, 166.28, 164.24, 138.75, 132.91, 132.32,
130.97, 130.28, 127.33, 125.45, 124.90, 114.24, 66.41, 55.68
ppm. HRMS (ESI-TOF): m/z calcd for C16H14O4S [M – H]–:
301.0529; found: 301.0539.
NMR (126 MHz, CDCl3): δ = 191.95, 165.50, 140.93, 138.37,
132.78, 130.41, 130.31, 128.86, 128.54, 124.88, 124.14, 123.11,
109.75 ppm.* HRMS (ESI-TOF): m/z calcd for C15H10O2S [M – H]–:
253.0318; found: 253.0323.
Compound 7b: yield 27 %. 1H NMR (500 MHz, CDCl3): δ = 13.75–
13.59 (br s, 1 H), 8.13–8.08 (m, 2 H), 8.07–8.04 (m, 1 H), 7.77–
7.72 (m, 1 H), 7.57–7.52 (m, 1 H), 7.46–7.40 (m, 1 H), 7.05–7.00
(m, 2 H), 3.97–3.83 (s, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ =
190.47, 165.41, 163.48, 140.58, 130.99, 130.84, 130.51, 130.11,
124.83, 124.03, 123.05, 114.17, 109.35, 55.69 ppm. HRMS (ESI-
TOF): m/z calcd for C16H12O3S [M – H]–: 283.0423; found:
283.0431.
(21) Chan, S. L.-F.; Low, K.-H.; Yang, C.; Cheung, S. H.-F.; Che, C.-M.
Chem. Eur. J. 2011, 17, 4709.
(22) Pan, B.; Ren, P.; Song, H.; Wang, Z. Synth. Comm. 2013, 43, 1337.
(23) Xiong, R.; Zhao, J.; Gutgesell, L. M.; Wang, Y.; Lee, S.; Karumudi,
B.; Zhao, H.; Lu, Y.; Tonetti, D. A.; Thatcher, G. R. J. J. Med. Chem.
2017, 60, 1325.
(19) Soural, M.; Krchnak, V. J. Comb. Chem. 2007, 5, 793.
(20) Phenacyl ester 6a or 6b (0.48 mmol) was dissolved in neat TFA
(1.5 mL), and the reaction mixture was heated to reflux for 3.5 h
in a sealed vessel. After completion of reaction, the TFA was
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E