A new microwave-assisted thionation-heterocyclization process leading to benzo[c]thiophene-1(3H)-thione and 1H-isothiochromene-1-thione derivatives

Article abstract of DOI:10.1039/c6ra01329e

The first example of a tandem thionation/S-cyclization process leading to benzo[c]thiophene-1(3H)-thione and 1H-isothiochromene-1-thione derivatives, starting from 2-alkynylbenzoic acids, is reported. The reaction is carried out in CH₂Cl_2<

Full text of DOI:10.1039/c6ra01329e

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DOI: 10.1039/C6RA01329E.
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DOI: 10.1039/C6RA01329E
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A new microwave-assisted thionation-heterocyclization process
leading to benzo[c]thiophene-1(3H)-thione and
1H-isothiochromene-1-thione derivatives
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
b
c
d
Salvatore V. Giofrè,* Roberto Romeo, Raffaella Mancuso,* Nicola Cicero, Nicola Corriero,
Ugo Chiacchio,e Giovanni Romeoa and Bartolo Gabriele*b
DOI: 10.1039/x0xx00000x
www.rsc.org/
The first example of a tandem thionation/S-cyclization process reported in the literature for the synthesis of O- or N-
leading to benzo[c]thiophene-1(3H)-thione and 1H- heterocycles (Scheme 1, Y = O or NR), there are still relatively
isothiochromene-1-thione derivatives, starting from 2- few examples of heterocyclizations of S-containing alkyne
alkynylbenzoic acids, is reported. The reaction is carried out in substrates leading to sulfur heterocycles (Scheme 1, Y = S). This
CH2Cl2 using 1 equiv of the Lawesson’s reagent under MW is probably connected with the relatively low stability of the
irradiation at 100 °C and 300 W for 1 h. Depending on the nature thiol group as compared to the hydroxyl or the amino group
of the substituent at the distal  carbon of the triple bond, either and, in the case of metal-catalyzed heterocyclization, to the
benzothiophenethiones or isothiochromenethiones were obtained “poisoning” effect exerted by the sulfur atom on the metal
selectively, in high to excellent yields. The structure of catalyst, owing to its strong coordinating and adsorptive
representative compounds has been confirmed by X-ray properties.2
diffraction analysis.
Heterocyclization of acetylenic substrates bearing a suitably
R
R
CR
SH
CHR
placed nucleophilic group is widely recognized as
a
Y
Y
Y
methodology of primary importance for the direct preparation
of a variety of heterocyclic systems in a regioselective fashion,
starting from readily available acyclic precursors.1 This reaction
can be promoted by strongly basic conditions, which favor the
deprotonation of the nucleophilic group, followed by
intramolecular nucleophilic attack to the triple bond (Scheme
1, pathway a; only the exo-dig mode is shown for simplicity).
To avoid possible substrate and/or product degradation, the
heterocyclization is more conveniently carried out by
electrophilic activation of the triple bond, usually ensuing from
triple bond coordination to a suitable metal center (as in
metal-catalyzed heterocyclizations, Scheme 1, pathway b) or
from the interaction with an electrophilic species (such as
iodine, as in the case of iodocyclization reactions that lead to
iodinated heterocycles, Scheme 1, pathway c).
a
B
I
I
H+
I2
R
R
YH
Mn+
I
c
YH
Y
b
Mn+
M(n-1)+
H+
Mn+
H+
R
R
R
YH
Y
Y
(YH = heteronucleophile; B = strong base;
Mn+ = metal center; SH = protic solvent)
Scheme 1. Possible heterocyclization pathways of acetylenic substrates
bearing a heteronucleophilic group (YH) leading to heterocycles (only the
exo-dig mode is shown for simplicity).
Compared to the considerable number of examples
Nevertheless, during the last years, several important S-
cyclization reactions, starting from substrates bearing a free as
well as a masked thiol group, have been developed,1a,3
including several contributions from our research group.3b,I,,j, 4
In this work, we report a new thionation-heterocyclization
process leading to benzo[c]thiophene-1(3H)-thione and 1H-
a.Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche ed Ambientali,
Università di Messina, Via S.S. Annunziata, 98168 Messina, Italy. E-mail:
sgiofre@unime.it
b.Laboratory of Industrial and Synthetic Organic Chemistry (LISOC), Dipartimento di
Chimica e Tecnologie Chimiche, Università della Calabria, Via P. Bucci, 12/C,
87036 Arcavacata di Rende (CS), Italy. E-mail: raffaella.mancuso@unical.it;
bartolo.gabriele@unical.it
c. Dipartimento di Scienze biomediche, odontoiatriche e delle immagini
morfologiche e funzionali, Università di Messina, Via Consolare Valeria, 98125
Messina, Italy.
isothiochromene-1-thione derivatives (2 and 3
, respectively)5-7
in one step starting from readily available 2-alkynylbenzoic
d.Istituto di Cristallografia, CNR, Via Amendola 122, 70126 Bari, Italy.
e. Dipartimento di Chimica, Università di Catania, Viale A. Doria, 95100 Catania,
Italy.
acids 18,9 (Scheme 2). The tandem process is carried out under
† Electronic Supplementary Information (ESI) available: Synthetic procedures,
characterisation of compounds, NMR spectra. See DOI: 10.1039/x0xx00000x
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J. Name., 2013, 00, 1-3 | 1
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microwave (MW) irradiation,10 in the presence of 1 equiv of substrate. A peculiar aspect of our MW-assisted synthetic
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the Lawesson’s reagent.11,12 2-alkynylbenzodithioic acids I 13
,
DOI: 10.1039/C6RA01329E
approach is that the S-cyclization of the intermediate 2-
obtained in situ by thionation of
give or without the need for activation from an external presence of an external electrophilic promoter.
electrophilic promoter (Scheme 2). The structure of products was elucidated by H NMR and
1, undergo S-cyclization to alkynylbenzodithioic acids I occurs without the need for the
2
3
1
2
13C NMR spectroscopies and MS spectrometry. In particular,
the Z stereochemistry around the exocyclic double bond was
assigned on the basis of selective 1D NOESY experiments,
carried out on compound 2a (Fig. 1A). When H4 was irradiated
(7.53 ppm), the selective 1D NOESY spectrum clearly showed
cross-peaks between H4 and H8 (7.94 ppm), H4 and Horto (7.62
ppm) in the phenyl substituent, as the result of the spatial
proximity of these protons, which is only possible if they are in
the Z-configuration. The Z stereochemistry was further
confirmed by X-ray crystallographic analysis (Fig. 2, see the
Supplementary Information for additional details).14
R2
R
R2
R
LR
(1 equiv)
SH
R1
CO2H
R1
CH2Cl2, 100 °C
MW, 300 W, 1 h
1
S
I
R2
R2
R
R
or
S
S
R1
R1
S
S
3
2
H3CO
S
S
S
P
P
S
OCH3
LR = Lawesson's Reagent
Scheme 2. MW-assisted tandem thionation-heterocyclization of 2-
alkynylbenzoic acids 1, carried out in the presence of 1 equiv of the
Lawesson’s reagent, that leads to (Z)-3-alkylidenebenzo[c]thiophene-1(3H)-
thiones 2 and 1H-isothiochromene-1-thiones 3 through the formation of 2-
alkynylbenzodithioic acids I as intermediates.
Figure 1. Molecular structure of compounds 2a and 3d optimized by
Gaussian at 6-31g**b3lyp level.
The
initial
substrate
we
tested
was
2-(2-
phenylethynyl)benzoic acid 1a (R1 = R2 = H, R = Ph), which was
allowed to react with 1 equiv of the Lawesson’s reagent in
CH2Cl2 at 100°C under MW irradiation. After 1 h, (Z)-3-
benzylidenebenzo[c]thiophene-1(3H)-thione 2a was obtained
in 90% isolated yield, with complete regio- and
stereoselectively (Scheme 3).
Our protocol could be also be successfully applied to
substrates substituted in ortho or in para with respect to the
carboxyl group, as in the case of 1b (R2 = Me) and 1c (R1 = Cl),
which led to the corresponding benzo[c]thiophene-1(3H)-
thiones 2b and 2c in 91% and 85% yields, respectively (Scheme
3). Moreover, a substrate bearing a p-fluorophenyl substituent
on the triple bond, such as 1f, led to the corresponding
benzo[c]thiophene-1(3H)-thione derivative 2f in high yield
(88%, Scheme 3).15
R2
R
5-exo-dig
S
R1
S
2a: R1 = R2 = H, R = Ph: 90%
2b: R1 = H, R2 = Me, R = Ph: 91%
R2
R
Lawesson's
reagent (1 equiv)
2c: R1 = Cl, R2 = H, R = Ph: 85%
2d: R1 = R2 = H, R = 4-MeOC6H4: 5%
2e: R1 = R2 = H, R = 4-pentyl-C6H4: 70%
2f: R1 = R2 = H, R = 4-F-C6H4: 88%
CH2Cl2, 100 °C
MW, 300 W, 1h
R1
CO2H
1a: R1 = R2 = H, R = Ph
1b: R1 = H, R2 = Me, R = Ph
1c: R1 = Cl, R2 = H, R = Ph
1d: R1 = R2= H, R = 4-MeOC6H4
1e: R1 = R2 = H, R = 4-pentyl-C6H4
1f: R1 = R2 = H, R = 4-F-C6H4
1g: R=Pr
R
S
6-endo-dig
S
3d: R = 4-MeOC6H4: 90%
3e: R = 4-pentyl-C6H4: 20%
3g: R = Pr: 86%
Figure 2. X-ray crystal structures of products 2a and 3d, showing 50%
probability ellipsoids for non-H atoms and spheres of arbitrary size for H
atoms.
Scheme 3. Synthesis of (Z)-alkylidenebenzo[c]thiophene-1(3H)-thiones 2 and
1H-isothiochromene-1-thiones 3.
It is worth noting that the same reaction, carried out under
conventional heating (refluxing CH2Cl2, 1,2-dichloroethane,
toluene or MeCN for 6-24 h) led to the formation of 2a in only
small amounts (0-5%), with partial decomposition of the
Interestingly, 2-alkynylbenzoic acids carrying on the triple
bond an alkyl substituent (such as propyl, as in 1g) or a phenyl
group substituted in the para position with a strong
-
donating group (such as methoxyl, as in 1d) selectively
2 | J. Name., 2012, 00, 1-3
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underwent, after in situ thionation, a 6-endo-dig rather than a
5-exo-dig cyclization, to give the corresponding 1H-
Conclusions
View Article Online
DOI: 10.1039/C6RA01329E
In summary, we have reported the first example of tandem
thionation /heterocyclization of 2-alkynylbenzoic acids . The
process occurs using 1 equiv of the Lawesson’s reagent as the
thionation agent under MW irradiation (100 °C at 300 W) in
CH2Cl2 for 1 h, and leads to (Z)-benzothiophenethiones
isothiochromenethiones
substituent at the distal
bond. In particular, compounds
stereoselectively obtained starting from substrates bearing an
aryl group (Ph, 4-F-C6H4, or 4-pentyl-C6H4) as substituent on
the carbon-carbon triple bond, through thionation followed by
a 5-exo-dig cyclization, while substrates carrying an alkyl group
(such as Pr) or an electron-rich aryl substituent (such as p-
MeOC6H4) at the same position selectively underwent a 6-
isothiochromene-1-thiones 3g and 3d
,
respectively, in
was
1
excellent yields (Scheme 3).16 The structure of products
3
confirmed by MS spectrometry, 1H NMR and 13C NMR
spectroscopies (in particular, no NOESY effect was observed by
irradiation of proton H4 in compound 3d, see Fig. 1B), and
confirmed by X-ray crystallographic analysis (Fig. 2; see the
Supplementary Information for additional details).14
2
or
, depending on the nature of the
position of the carbon-carbon triple
were regio- and
3

2
Quite consistently, a substrate bearing on the triple bond a
phenyl group substituted in para position with a weakly
electron-donating substituent (such as the n-pentyl, as in 1e
)
afforded (Z)-3-(4-pentylbenzylidene)benzo[c]thiophene-1(3H)-
thione 2e as the major product (70% yield) together with 3-(4-
pentylphenyl)-1H-isothiochromene-1-thione 3e in 20% yield
(Scheme 3). The observed change in regioselectivity moving
from an electron-withdrawing substituent to an electron-
donating substituent on the triple bond is in agreement with
the results previusoly obtained in other heterocyclizations of
functionalized alkynes.17
endo-dig cyclization to yield 3. The study of the bioactivity of
the newly synthesized S-heterocycles is currently underway
and will be reported in due course.
Mechanistically, the cyclization process may start with
Notes and references
MW-induced dissociation of the dithiocarboxyl group18 of
I
1
For recent reviews, see: (a) R. Mancuso and B. Gabriele,
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with simultaneous proton coordination by the triple bond,
with formation of intermediate II, as shown in Scheme 4. This
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bond, can lead to compound
of an electron withdrawing group at the
2
or
3
. In particular, the presence
carbon of the triple

bond promotes the protonation on this carbon followed by the
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dithiocarboxylate group, leading to the formation of
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product . Alternatively, the presence of an electron releasing
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of the triple bond ( carbon), thus leading to the formation of
2. An anti intramolecular attack is in perfect
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
2
3

1H-isothiochromene-1-thione derivatives 3.
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P. Gogoi, K. Indukuri and A. K. Saikia, J. Org. Chem., 2015, 80
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2641; (b) R. Mancuso, C. S. Pomelli, C. Chiappe, R. C. Larock
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H
R2
R
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R
R
R2

MW
anti 5-exo-dig

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S
SH
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R1
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S
S
S
2
I
II
(favored for R = Ph,
4-F-C6H4, 4-pentyl-C6H4)
6-endo-dig
J. Dabdoub and A. C. M. Baroni, Tetrahedron Lett., 2014, 55
,
R2
52; (f) C. R. Reddy, R. R. Valleti and M. D. Reddy, J. Org.
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Scheme 4. Proposed mechanism for the heterocyclization of 2-
alkynylbenzodithioic acids I: the initial MW-induced dissociation of the
dithiocarboxyl group, with simultaneous proton coordination by the triple
bond, is followed by anti 5-exo-dig or by 6-endo-dig intramolecular
nuclophilic attack of the dithiocarboxylate group to the electrophilically-
activated triple bond.
Han, H. Jiang and Y. Yamamoto, Tetrahedron Lett., 2012, 53
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,
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This journal is © The Royal Society of Chemistry 20xx
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Gut’yar and G. P. Baitursynova, Russ. J. Org. Chem., 2015, 51
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1H-Isothiochromene-1-thione derivatives (isothiocumarin-
never been reported for similar S-heterocyclization
reactions.
6
7
thiones) have been previously obtained by iodine-mediated 13 Thioacids are a well-established and versatile class of organic
cyclization of lithium 2-(vinyl)dithiobenzoate derivatives: (a)
S. Fukumachi, H. Konishi and K. Kobayashi, Heterocycles,
2009, 78, 169, or by treatment of 2-chloro-N-cyanomethyl-N-
methyl-5-nitrobenzamide with sodium hydride in DMSO or
DMF and carbon disulfide: (b) W. Dolling, M. Biedermann
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8
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3-Alkylidenebenzo[c]thiophene-1(3H)-thione
and
(
)
(3d) contain the
isothiochromene-1-thione derivatives constitute promising
classes of heterocycles, with potential pharmacological
applications, in view of the known biological activities
supplementary crystallographic data for this paper. These
data are provided free of charge by The Cambridge
Crystallographic Data Centre.
(including anti-ischemic and anti-cancer activity) shown by 15 The selectivity toward the 5-exo-dig products 2a-c and 2f
their O,S-analogues; see, for example: (a) J. Wu, L. Ling, X.
Wang, T. Li, J. Liu, Y. Lai, H. Ji, S. Peng, J. Tian and Y. Zhang, J.
was virtually complete; in fact, no detectable amounts of the
isomeric products deriving from a 6-endo-dig cyclization
mode were observed in the reaction crudes by GLC and
GLC/MS analyses.
Med. Chem. 2012, 55
, 7173; (b) D. Kaminskyy, A.
Kryshchyshyn, I. Nektegayev, O. Vasylenko, P. Grellier and R.
Lesyk, Eur. J. Med. Chem., 2014, 75, 57.
2-Alkynylbenzoic acids were easily prepared by Sonogashira
coupling between methyl 2-iodobenzoates (prepared by
esterification of commercially available 2-iodobenzoic acids)
16 The selectivity toward the 6-endo-dig product 3g was
practically complete, while small amounts of the 5-exo-dig
cyclization product 2d (5%) were observed in the reaction
8
mixture deriving from 1d
.
and 1-alkynes followed by hydrolysis: see the experimental 17 See, for example: B. Gabriele, G. Salerno, A. Fazio and R.
section for details. For representative recent examples of Pittelli, Tetrahedron, 2003, 59, 6251.
Sonogashira coupling conditions, see (a) R. Romeo, S. V. 18 The ionization of a benzodithioic acid is a well-known
Giofrè, A. Garozzo, B. Bisignano, A. Corsaro and M. A.
Chiacchio, Bioorg. Med. Chem., 2013, 21, 5688; (b) R. Romeo,
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Chem., 2014, 5442.
The heterocyclization of 2-alkynylbenzoic acids and their
derivatives has been of great significance for the formation
of heterocyclic compounds such as isocoumarins, 3-
process [for a recent paper, see, for example: J. Vandanapu
and S. Rachuru, Adv. Phys. Chem., 2012, Article ID 598243
(doi:10.1155/2012/598243).
9
alkylidenephthalides,
aryl(alkyl)idene-isoindolones,
2H-isoquinolin-1-ones,
3-
3-benzazepinones,
isoindolinones and isobenzofuranimines; for representative
recent examples, see: (a) R. Mancuso, I. Ziccarelli, D.
Armentano, N. Marino, S. V. Giofrè and B. Gabriele, J. Org.
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,
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4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C6RA01329E
Table of Contents Entry
R2
R
H3CO
S
S
S
P
P
+
R1
CO2H
S
CH2Cl2
100 °C, 1 h 300 W
MW
OCH3
(R = Pr, 4-MeO-C6H4)
R2
(R = Ph, 4-F-C6H4,
4-pentyl-C6H4)
R2
R
R
S
S
R1
R1
(up to 90%)
S
S
(up to 91%)
The first example of a MW-assisted tandem thionation/S-cyclization process, leading to
benzothiophenethione and isothiochromenethione derivatives, is reported.