Synthesis of Tetrahydrothiopyrano[2,3-b]indole [60]Fullerene Derivatives via Hetero-Diels–Alder Reaction of C60 and α,β-Unsaturated Indole-2-thiones

Article abstract of DOI:10.1002/jhet.2653

Hetero-Diels–Alder reactions of [60]fullerene with α,β-unsaturated thio-oxindoles (3a, 3b, 3c), prepared from thio-oxindole 1 and heteroaromatic aldehydes (2a, 2b, 2c), to generate tetrahydrothiopyrano[2,3-b]indole [60]fullerene cycloadducts (5a, 5b, 5c) under thermal or microwave irradiation were described. The yields were improved, and the reaction time was decreased by conducting the reaction under microwave irradiation.

Full text of DOI:10.1002/jhet.2653

Month 2016
Synthesis of Tetrahydrothiopyrano[2,3-b]indole [60]Fullerene Derivatives
via Hetero-Diels–Alder Reaction of C60 and α,β-Unsaturated Indole-2-thiones
a
a
a
b
*
Firouz Matloubi Moghaddam, Bahram Ghanbari, Masoumeh Behzadi, and Mohammad Hadi Baghersad
aLaboratory of Organic Synthesis and Natural Product, Department of Chemistry, Sharif University of Technology,
P.O. Box 11155-9516, Tehran, Iran
bDepartment of Chemistry, Kharazmi University, P.O. Box 15719-14911, Tehran, Iran
*
E-mail: masome.behzadi@gmail.com
Received April 13, 2015
DOI 10.1002/jhet.2653
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
Hetero-Diels–Alder reactions of [60]fullerene with α,β-unsaturated thio-oxindoles (3a–c), prepared from
thio-oxindole 1 and heteroaromatic aldehydes (2a–c), to generate tetrahydrothiopyrano[2,3-b]indole [60]ful-
lerene cycloadducts (5a–c) under thermal or microwave irradiation were described. The yields were im-
proved, and the reaction time was decreased by conducting the reaction under microwave irradiation.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
transition-metal catalyzed methodology for Diels–Alder
cycloaddition of C60 has been underdeveloped. Therefore,
the number of publications in metal-catalyzed [4+2] cyclo-
addition of [60]fullerene is limited.
Hence, the research interest on the functionalization of
[60]fullerene with heterodienes has been augmented be-
cause of its unique spherical structure. One of the most
powerful methods for the preparation of organo-
fullerenes bearing a six-member heterocycle is the
[4+2] cycloaddition reaction of [60]fullerene with
heterodienes [16].
The synthesis of such compounds has been a focus in or-
ganic chemistry for more than two decays [17]. Two impor-
tant limitations have been known for the most of the
classical synthetic methods employing for these
compounds. Firstly, the isolated yield for heterocycle-fused
[60]fullerene derivatives are very low, and the researchers
try to improve it. Secondly, the reaction time for these reac-
tions was typically very long. It is remarkable that
microwave-assisted synthesis dramatically shortened the
reaction time needed compared with those by conventional
heating [18] Furthermore, the yield of [60]fullerene deriva-
tives also increased when microwave was applied [19]. For
instance, the hetero-Diels–Alder reactions of [60]fullerene
fused dihydropyran [20] and dihydrothiopyran [21] deriva-
tives through C–O and C–S bond formations have been re-
ported by Eguchi and coworkers.
The discovery of fullerenes as the first molecular allo-
trope of carbon [1] influenced many aspects of contempo-
rary chemistry in the last two decades. These useful
carbon-building blocks [2] with spherical symmetry, dis-
play potential applications in nanomaterial sciences [3],
and medicinal chemistry [4]. In particular, the biological
activity, such as a DNA cleavage [5], enzyme inhibition
[6], and cytotoxicity [7] by generating singlet oxygen un-
der visible light, gives an idea of the unabated interest in
these three-dimensional molecules [8].
Besides the utility of [60]fullerene as biologically active
agents, it was shown that endohedral metallofullerenes
used as contrast agent in magnetic resonance imaging
(MRI) [9]. For example, gadolinium endohedral
metallofullerenes have been widely studied because of
their magnetic contrast-enhancing properties [9,10].
On the other hand, polymer–fullerene composites, or so-
called bulk heterojunctions [11] have been developed as
the most effective solar cells. The high electron affinity
and superior ability to transport charge make fullerenes
the best acceptor component currently available for these
devices [12].
Although the functionalization of [60]fullerene using or-
ganic methodologies is well established [13], studies of
transition metal-catalyzed reaction of fullerene function-
alization relatively poorly developed [14]. Pd-catalyzed
heteroannulations of [60]fullerene with o-iodoanilines and
anilides reported by Wang and coworkers [15]. The
Herein, we report a new synthetic route for the prepara-
tion of sulfur-bonded [60]fullerene derivatives 1 by [4+2]
cycloaddition reactions.
© 2016 Wiley Periodicals, Inc.

F. Matloubi Moghaddam, B. Ghanbari, M. Behzadi, and M. H. Baghersad
Vol 0000
Table 1
Organo [60]fullerene compounds 5 from α,β-unsaturated thio-oxindoles 3 and C60 4.
Classical heating
Microwavea
T
Time
(day)
Yield
(%)
T
Time
(min)
Yield
(%)
(°C)
(°C)
R
X
Product no.
Me
Me
Me
S
O
N
5a
5b
5c
Reflux
Reflux
Reflux
9
11
10
5
7
6
110
110
110
25
40
40
15 (35)b
5 (20)
10 (25)
aPower 800 W.
bBased on recoverd C60
.
RESULTS AND DISCUSSION
yields and high purity. The results are summarized in
Table 1.
As a part of ongoing interest in the study and synthesis of
heterocycle-fused [60]fullerene compounds [16], we were
encouraged to undertake the synthesis of tetrahydro-
thiopyrano [2,3-b] indole [60]fullurene derivatives, starting
with an appropriate derivatives of α,β-unsaturated thio-
oxindoles (3a–c) and [60]fullerene. The results are summa-
rized in Table 1. α,β-Unsaturated thio-oxindoles (3a–c) ob-
tained via hetero-Diels–Alder reaction of thio-oxindoles 1
with heteroaromatic aldehydes (2a–c) (Scheme 1) [22].
As can be seen in Table 1, a wide range of α,β-
unsaturated thio-oxindoles (3a–c) and C60 4 were refluxed
in toluene as solvent for 9–11 days to give the correspond-
ing tetrahydrothiopyrano[2,3-b]indole [60]fullurene (5a–c)
with low yields and high purity (Scheme 2).
To assist improving the yield of the products and de-
creasing the reaction time, the reaction was further inves-
tigated under microwave irradiation. A mixture of α,β-
unsaturated thio-oxindoles (3a–c) and C60 4 were reacted
with molar ratio of 1:1.4 in dry Ortho Dichloro Benzene
(ODCB)-toluene (1mL). The reaction was screened un-
der microwave irradiation for 25–50 min at 110°C,
800W. The reaction progress was monitored by TLC in
5-min intervals. The reaction proceeded with moderate
Generally, microwave-assisted reactions were carried
out dielectric heating resulted from dipole–dipole interac-
tions between polar molecules and microwave electromag-
netic field. In this work, both solvent and reactants
(α,β-unsaturated thio-oxindoles and [60]fullerene) are po-
lar molecules that absorb microwave irradiation simulta-
neously so that the reaction proceeds via the microwave
heating [23] (Scheme 3).
The structure of 5a–c was unambiguously determined
1
from H NMR and 13C NMR spectra in addition, UV–
vis, and FTIR data. The UV–vis spectrum contained sig-
nals around at 215, 255, 316, 436 (characteristic of the
1:1 cycloadduct of [60]fullerene), and 615 nm. The weak
absorption band of dihydrofullerenes around at 430nm,
confirming the presence of the [6,6] isomer.
The 13C NMR spectra of compound 5a show signals due
to two sp3 junction carbons at 84 and 75ppm. In addition
1
to the aromatic protons, the required H NMR signals of
cycloadducts 5a–c appeared around 6.0 ppm (CH) and
3.9 ppm (N-CH3).
A plausible mechanism for the formation of products (5a–
c) is concerted and syn-addition, which is in accordance with
the proposed mechanism for Diels–Alder reaction.
Scheme 1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Hetero-Diels–Alder Reaction of C60 and α,β-Unsaturated Indole-2-thiones
Scheme 2
Scheme 3
CONCLUSION
completed in 25–50min that is much faster than the thermal
reaction (9–11days) under the same condition showing that
the reaction is assisted by microwaves. Therewith, the yields
of products were enhanced under microwave irradiation.
Summarily, easily prepared α,β-unsaturated indolin-
2-thiones proved to be appropriate materials for the
synthesis of new macrocycle tetrahydrothiopyrano [2,3-
b] indole [60]fullurene (5a–c) derivatives via [4+2] cy-
cloaddition reaction. This reaction demonstrates that the
hetero-Diels–Alder reaction of α,β-unsaturated indolin-2-
thione compound is applicable to [60]fullerene, giving
an irreversible cycloadduct, and a C–S bond can be
formed on the [60]fullerene surface. Organofullerenes
(5a–c) are thermodynamically stable compounds because
of the aromatic character of the resulting cycloadduct,
thus avoiding the undesired cycloreversion process ob-
served in other C60-based Diels–Alder reactions [24]. In
particular, various substituents can be introduced on the
heterocycle by employing some kinds of reagents. o-
quinodimethanes [25], o-Quinone methide imines [26],
and the heterocyclic analogs [27] have been successfully
used to obtain stable heterocyclic organofullerenes. The
driving force for this study was the novelty of the annu-
lation of sulfur heterocycles to C60 core. To the best of
our knowledge, this is also the first report of the synthe-
sis of thiopyrano [2,3-b] indole [60]fullurene. Further-
more, under the defined reaction conditions, the
cyclization process does not require the application of
transition metals as catalyst or additives. High stereo-
selectivity, easy work-up, and single-step nature of the
methodology are among the main advantages of the pro-
posed procedure.
EXPERIMENTAL
All required chemicals were purchased from Merck and
Fluka (Sigma-Aldrich, Darmstadt, Germany) chemical
companies. All of the known compounds were identified
by comparison of their spectral data and physical proper-
1
ties with those of the authentic samples. H NMR and
13C NMR spectra were recorded on a Bruker (Billerica,
MA) DRX-300 AVANCE NMR spectrometer using
CDCl3 as a solvent and using tetramethylsilane (TMS) as
an internal standard. Chemical shifts were reported in parts
per million (δ) downfield from TMS. All coupling con-
stants (J) are in hertz. IR spectra were recorded on Mattson
(Fremont, CA) 1000 FT-IR spectrometer using KBr
pellets. Elemental analyses were run on a Perkin-Elmer
(Waltham, MA) USA-2400 series. Column chromatogra-
phy was performed on silica gel 40 [Merck (Kenilworth,
NJ), 70–230mesh]. TLC plate was carried out on silica
gel 60 Gf-254 analytical sheets. Microwave-assisted reac-
tions have carried out using microwave reactor [Milestone
(Shelton, CT) multimode]. [60]fullerene (98%) was pur-
chased from Bucky (Seattle, WA) company.
Synthesis of fullerene nanoparticle (4).
Fullerene
nanoparticle 4 were prepared in large scale by arc
vaporization of graphite [28].
Preparation of α,β-unsaturated indolin-2-thiones (3a–c). To
a flask containing 1mmol of thio-oxindole 1 in toluene
(5mL), 1.2mmol of heteroaromatic aldehydes 2a–c was
Having a comparison between thermal-assisted and
microwave-assisted reactions, the reaction was also per-
formed under microwave irradiation. In one representative
case, the reaction under microwave irradiation was
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

F. Matloubi Moghaddam, B. Ghanbari, M. Behzadi, and M. H. Baghersad
Vol 0000
added in refluxing temperature for 4–5 h. The progress of the
reaction was followed up by TLC whose spots were
visualized either with UV light or with Iodine stabilized on
silica gel. Reaction mixture was stirred for a given reaction
time, and then, the solvent was removed under reduced
pressure, and the residue was purified by column
chromatography eluted with hexane-ethyl acetate.
J2 = 1.4 Hz, 2H, furan ring), 7.71 (dd, J1 =3.6 Hz,
J2 = 1.2 Hz, 1H, furan ring); 13C NMR (CDCl3): δ (ppm)
55.0 (N-CH3), 75.1 (CH), 77.2, 84.1 (2C sp3); UV–vis
(toluene) λmax (nm): 272, 385, 432; Anal. Calcd for
C53H23NOS: C, 88.24; H, 3.20; N, 1.95; O, 2.22; S,
4.42. Found: C, 88.19; H, 3.21; N, 1.94; O, 2.22; S, 4.44.
Tetrahydrothiopyrano-4-pyrolyl-[2,3-b]indole [60]fullurene
General procedure for the synthesis of tetrahydro-
thiopyrano [2,3-b] indole [60]fullurene (5a–c) by classical
(5c).
Brown solid (hexane/ethyl acetate); 10% (25%
based on consumed C60); IR (KBr, υmax cm1): 1377,
1
heating.
In a round bottom flask equipped with a
1261, 1096, 800, 767, 526; H NMR (CDCl3): δ (ppm)
stirring magnetic bar and a condenser, α,β-unsaturated
indolin-2-thiones (3a–c) (0.079 mmol) and C60 4 (40 mg,
0.055 mmol) were mixed in dry toluene (70 mL). The
suspension was stirred and refluxed for 9–11 days. The
reaction is monitored with TLC and UV–vis spectrum.
After completion of the reaction, obtaining compounds
(5a–c) as brown solids that finally were washed with
ethyl acetate for recovering C60 unreacted. Afterward, the
adducts were purified using column chromatography
(hexane/EtOAc) from another byproducts, which
4.10 (m, 3H, NCH3) 6.69 (s, 1H, CH
tetrahydrothiopyrane ring), 7.11–7.14 (m, 4H, aromatic),
7.44–7.46 (dd, J1 = 3.8 Hz, J2 = 2.5 Hz, 2H, pyrrol ring),
7.61–7.65 (dd, J1 = 2.5 Hz, J2 = 1.4 Hz, 1H, pyrrol ring);
UV–vis (toluene) λmax (nm) 356, 436; Anal. Calcd for
C53H24N2S: C, 88.28; H, 3.36; N, 3.92; S, .4.42. Found:
C, 88.31; H, 3.36; N, 3.89; S, 4.45.
Acknowledgments. This work was supported by grants from the
Research Council of Sharif University of Technology.
identified with experimental analysis.
General procedure for the synthesis (5a-c) by microwave
heating.
For investigation of the reaction under
microwave irradiation, solution of C60 (40mg,
a
REFERENCES AND NOTES
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for that of traditional heating products. The resulting brown
solution was washed with ethyl acetate, dried, and
evaporated to dryness under reduced pressure. The residue
was chroma-tographed on a silica gel column with hexane/
ethylacetate as eluent.
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