An efficient approach for the synthesis of functionalized selenoethers and selenacalix[4]thiophenes, {2,5-(μ-Se)(3,4-dialkoxythiophene)}4

Article abstract of DOI:10.1016/j.tetlet.2014.08.005

An efficient method for the synthesis of selenoethers and selenacalix[4]thiophene utilizing SeCl₂is described. Reactions of phenols with SeCl₂produce the corresponding selenoethers in moderate to good yields. The selenacalix[4]thioph

Full text of DOI:10.1016/j.tetlet.2014.08.005

Tetrahedron Letters 55 (2014) 5232–5235
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient approach for the synthesis of functionalized selenoethers
and selenacalix[4]thiophenes, {2,5-(l-Se)(3,4-dialkoxythiophene)}4
Pawan Kumar a, Vitthalrao S. Kashid a, Joel T. Mague b, Maravanji S. Balakrishna a,
⇑
a Phosphorus Laboratory, Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400 076, India
b Department of Chemistry, Tulane University, New Orleans, LA 70118, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient method for the synthesis of selenoethers and selenacalix[4]thiophene utilizing SeCl2 is
described. Reactions of phenols with SeCl2 produce the corresponding selenoethers in moderate to good
yields. The selenacalix[4]thiophenes, [–Se-3,4-(C4(OR)2S)]4 (R = CH3, C6H13) were synthesized by conve-
nient one-pot electrophilic aromatic substitution reaction of dialkoxy thiophene with SeCl2 in good yield.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 10 July 2014
Revised 1 August 2014
Accepted 3 August 2014
Available online 8 August 2014
Keywords:
Selenoethers
Selenacalix[4]thiophenes
Selenamacrocycles
Selenacalixarenes
In the last few decades, significant attention has been paid to
the synthesis and applications of selenoethers and selenamacrocy-
cles.1 They are potentially active as antioxidants,2 antitumor,3 anti-
infective agents,4 enzyme inhibitors,5 glutathione peroxidase mim-
ics,6 and immunomodulators.7 These compounds also find applica-
tions in semiconductor materials and metal ion sensors.8
Methodologies followed for the synthesis of these selenoethers
mostly include the reactions of metal selenides with aryl halides
or the conversion of aryl halides to aryl lithium salts and subse-
quent reaction with suitable electrophiles.9 In some of the early
reports, SeOCl2 has also been used but lesser yield and laborious
separation are the major drawbacks (Chart 1).10
methylenes from traditional calixarenes by heteroatoms not only
modulates the cavity size, and shape but also provides additional
binding site for guest atoms. Among them, aza-,12 oxa-,13 and thi-
acalixarenes14 are the most studied analogues, while selenacalixa-
renes are the least studied.15 Despite the interesting possibilities,
Heteracalixarenes are proven as an important molecular archi-
tecture in the field of supramolecular chemistry.11 Replacement of
R' Se
Se
R
RX
i) R'SeNa
R
Li
Se(dtc)2
ii)
R
R
R
R
OH
R
OH
OH
SeOCl2
CHCl3
Se
iii)
Figure 1. Molecular structure of selenoethers, [(HOC10H6)2(
OC10H6)2( -Se)] (2). All hydrogen atoms have been omitted for clarity. Thermal
ellipsoids are drawn at 50% probability level. Selected bond lengths (Å) and angles
(°) for [(HOC10H6)2( -Se)] (1) : Se1–C11 = 1.9241(16), Se1–C1 = 1.9246(18), O1–
C2 = 1.3618(19), O2–C12 = 1.370(2), C11–Se1–C1 = 100.33(6), C2–O1–H1 = 109.5,
C12–O2–H2 = 109.5. [(CH3OC10H6)2( -Se)] (2): Se1–C1 = 1.921(5), Se1–
l-Se)] (1), and [(CH3-
l
l
Chart 1.
l
C11 = 1.928(4), O1–C20 = 1.361(5), O2–C10 = 1.357(5), C11–Se1–C1 101.37(18),
C20–O1–C21 = 118.5(3), C10–O2–C22 = 118.0(3).
⇑
Corresponding author.
http://dx.doi.org/10.1016/j.tetlet.2014.08.005
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

P. Kumar et al. / Tetrahedron Letters 55 (2014) 5232–5235
5233
selenoethers through electrophilic aromatic substitution reactions
using SeCl2 as electrophile. This methodology is found to be useful
0.5 SeCl2
,
diethyl ether
OR
OR
Se
AlCl3
OR
for the synthesis of selenacalix[4]thiophenes, {2,5-(
l-Se)(3,4-
dialkoxythiophene)}4 in good yield.
R= H 2-Naphthol
SeCl2 was prepared in situ by dropwise addition of SO2Cl2 to the
suspension of elemental selenium in THF at 0 °C. Freshly prepared
SeCl2 is pure enough to carry out further reactions. Dropwise
addition of SeCl2 to the diethyl ether solution of 2-naphthol in
the presence of catalytic amounts of AlCl3 yielded the pure selen-
R= Me 2-Methoxynaphthalene
tBu
R= H, 1 R= CH3, 2
tBu
tBu
0.5 SeCl2
,
obis(2,20-naphthol), [(HOC10H6)2( -Se)] (1) in 56% yield. The 77Se
l
THF
tBu
Reflux
NMR spectrum of 1 consists of a single resonance at 35.3 ppm.
Se
tBu
tBu
OH
Similar reaction of SeCl2 with 2-methoxynaphthalene yielded
OH
HO
2,4-ditertiarybutyl phenol
3
selenobis(2,20-methoxynaphthalene [(CH3OC10H6)2(
l-Se)] (2) in
47% yield as a yellow solid. The 77Se NMR spectrum of 2 showed
a single resonance at 114.5 ppm.
OH
OH
OH
OH
0.5 SeCl2
,
THF
THF
HO
HO
Single crystals of selenoethers 1 and 2 were grown from the sat-
urated solution of petroleum ether (bp 65–85 °C) for X-ray diffrac-
tion study.17 In the molecular structures of 1 and 2 (see Fig.1), the
two naphthol rings are bridged by selenium atom at 2-positions
with C11–Se1–C1 bond angles of 100.33(6)° and 101.37(18)°,
respectively. The Se–C11, Se–C1 bond lengths in 1 and 2 are
1.9241(6) and 1.9246(18) Å and 1.928(4) &1.921(5) Å, respectively.
To understand the effect of substituents on the reactivity of
phenols the similar reaction was carried out with 2,4-di-tert-butyl-
phenol (Scheme 1). The corresponding 2,20-selenobis(4,6-di-
tert-butyl phenol) (3) was isolated in moderate yield even under
refluxing conditions but with prolonged time. Compound 3 is a
white crystalline solid which is purified by column chromatogra-
phy. The 77Se NMR spectrum of compound 3 consists of a single
resonance at 148 ppm. Slow addition of half equivalent of in situ
prepared SeCl2 to the diethyl ether solution of 1,3,5-trihydroxy-
benzene has yielded 2,20-selenobis(1,3,5-trihydroxybenzene) (4)
Se
HO
OH
Phloroglucinol
OH
OH
4
1.5 SeCl2
,
Insoluble Polymer
HO
OH
5
Scheme 1.
the reports on these macromolecules are less extensive and the
synthesis is still challenging.16 Unlike other calixarenes, the
methods applicable for the synthesis of selenoethers have not been
extended effectively for the synthesis of selenacalixarenes. In
this Letter, we report a ‘one-pot’ synthesis of functionalized
RO
Se
OR
Se
RO
OR
S
S
OR
OR
SeCl2
,
RO
RO
S
S
diethyl ether
S
Se
Se
3,4-bis(alkoxy)thiophene
R = CH3, C6H13
RO
R = CH3 , C6H13
OR
6
7
RO
OR'
Se
RO
Se
OR'
Se
Se
S
RO
OR'
S
S
S
S
OR'
OR
OR
RO
R'O
RO
SeCl2
,
S
S
S
S
OR'
R'O
diethyl ether
Se
Se
Se
Se
OR
3-(hexyloxy)-4-methoxythiophene
R = C6H13, R' = CH3
R'O
OR
R'O
9
8
RO
Se
OR'
RO
Se
OR'
Se
Se
S
S
S
OR'
OR
OR
R'O
RO
RO
R'O
S
S
S
S
OR'
S
Se
Se
OR
Se
Se
OR'
R'O
RO
11
10
Scheme 2.

5234
P. Kumar et al. / Tetrahedron Letters 55 (2014) 5232–5235
with two rings inclined above the plane and two below the plane.
Selenacalix[4]thiophene 6 provides two different types of binding
sites for metals. It has a central core with four sulfur atoms and four
pincer type OSeO binding sites involving alkoxy oxygen atoms.
In conclusion, selenoethers and selenacalix[4]thiophene were
synthesized selectively in high yield. Selenacalix[4]thiophenes 6
and 7 are rare examples of selenium heteracalixarenes. Easy and
high yielding synthetic methodology can be extended to selenium
based supramolecular chemistry and related applications. Post
modification of selenacalix[4]thiophene and the development of
other classes of selenacalixarenes by this method and also their
interactions with transition metals, non-metal ions, and other
molecules are in progress.
Acknowledgments
We are grateful to the Department of Science and Technology
(DST), New Delhi, for financial support of this work through Grant
SR/S1/IC-17/2010. P.K. and V.S.K. thank CSIR-UGC, New Delhi for
Research Fellowship (JRF & SRF). We also thank the Department
of Chemistry Instrumentation Facilities, IIT Bombay, for spectral
and analytical data and J.T.M. thanks the Louisiana Board of
Regents for the purchase of the CCD diffractometer and the Chem-
istry Department of Tulane University for support of the X-ray
laboratory.
Figure 2. Molecular structure of selenacalix[4]thiophene, {2,5-(l-Se)(3,4-dime-
thoxy thiophene)}4 (6). All hydrogen atoms have been omitted for clarity. Thermal
ellipsoids are drawn at 50% probability level. Selected bond lengths (Å) and angles (°):
Se1–C1 = 1.907(5), Se1–C10 = 1.900(5), Se2–C7 = 1.897(5), Se2–C4 = 1.910(6),
S1–C1 = 1.711(6), S1–C4 = 1.732(5), S2–C10 = 1.714(5), S2–C7 = 1.726(5), O1–C2 =
1.370(6), O1–C5 = 1.440(6), C10–Se1–C1 = 98.1(2), C7–Se2–C4 = 99.4(2), C1–S1–C4 =
92.1(3), C10–S2–C7 = 92.7(2), C2–O1–C5 = 113.5(4), C3–O2–C6 = 114.5(4).
as light brown solid in good yield, while the treatment of SeCl2
with 1,3,5-trihydroxy benzene in 3:2 molar ratio has yielded the
polymeric {2,4,6-triseleno(1,3,5-trihydroxy benzene)}n (5) as an
insoluble yellow solid. The 77Se NMR spectrum of 4 shows a single
resonance at ꢀ35.8 ppm. Spectroscopic studies of 5 could not be
carried out because of poor solubility in most of the organic sol-
vents. However, the structural composition was established by ele-
mental analysis data.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
08.005.
References and notes
The reaction of 3,4-dimethoxythiophene with an equimolar
amount of SeCl2 in diethyl ether produced exclusively selenaca-
1. (a) Murray, S. G.; Hartley, F. R. Chem. Rev. 1981, 81, 365–414; (b) Hope, E. G.;
Levason, W.; Murray, S. G.; Marshall, G. L. J. Chem. Soc., Dalton Trans. 1985,
2185–2190; (c) Bochu, C.; Couture, A.; Grandclaudon, P. J. Org. Chem. 1988, 53,
4852–4855; (d) Kraatz, H. B.; Jacobsen, H.; Ziegler, T.; Boorman, P. M.
Organometallics 1993, 12, 76–80; (e) Booth, D. G.; Levason, W.; Quirk, J. J.;
Reid, G.; Smith, S. M. J. Chem. Soc., Dalton Trans. 1997, 3493–3500; (f) Kumar, A.;
Rao, G. K.; Saleem, F.; Singh, A. K. Dalton Trans. 2012, 41, 11949–11977; (g)
Sharma, K. N.; Joshi, H.; Singh, V. V.; Singh, P.; Singh, A. K. Dalton Trans. 2013,
42, 3908–3918; (h) Paine, T. K.; Rentschler, E.; Weyhermuller, T.; Chaudhuri, P.
Eur. J. Inorg. Chem. 2003, 3167–3178; (i) Paine, T. K.; Weyhermuller, T.; Bothe,
E.; Wieghardt, K.; Chaudhuri, P. Dalton Trans. 2003, 3136–3144.
2. (a) Mugesh, G.; Singh, H. B. Chem. Soc. Rev. 2000, 29, 347–357; (b) Mugesh, G.;
du Mont, W.-W.; Sies, H. Chem. Rev. 2001, 101, 2125–2180; (c) Birringer, M.;
Pilawa, S.; Flohe, L. Nat. Prod. Rep. 2002, 19, 693–718; (d) De Silva, V.;
Woznichak, M. M.; Burns, K. L.; Grant, K. B.; May, S. W. J. Am. Chem. Soc. 2004,
126, 2409–2413; (e) Nogueira, C. W.; Zeni, G.; Rocha, J. B. T. Chem. Rev. 2004,
104, 6255–6286.
3. (a) El-Bayoumy, K. Cancer Res. 1985, 45, 3631–3635; (b) Nayini, J.; El-Bayoumy,
K.; Sugie, S.; Cohen, L. A.; Reddy, B. S. Carcinogenesis 1989, 10, 509–512; (c)
Fiala, E. S.; Joseph, C.; Sohn, O. S.; El-Bayoumy, K.; Reddy, B. S. Cancer Res. 1991,
51, 2826–2830.
4. (a) Goudgaon, N. M.; Schinazi, R. F. J. Med. Chem. 1991, 34, 3305–3309; (b) Ni,
L.; Schinazi, R. F.; Boudinot, F. D. Antiviral Res. 1995, 27, 39–47.
5. (a) Engman, L.; Stern, D.; Frisell, H.; Vessman, K.; Berglund, M.; Ek, B.;
Andersson, C.-M. Bioorg. Med. Chem. 1995, 3, 1255–1262; (b) Southan, G. J.;
Salzman, A. L.; Szabó, C. Life Sci. 1996, 58, 1139–1148.
lix[4]thiophene, {2,5-(
good yield (Scheme 2). Similar compound, {2,5-(
phene)}4 was isolated earlier in a trace amount as a side product
in the reaction of thiophene with a mixture of dithienyl diselenide
and PhI(OAc)2.18 Compound 6 is a yellow solid soluble in most of
the organic solvents. Similarly, the reaction of 3,4-bis(hexyl-
l
-Se)(3,4-dimethoxythiophene)}4 (6) in
l-Se)(thio-
oxy)thiophene with freshly prepared SeCl2 gave {2,5-(l-Se) 3,4-
bis(hexyloxy)thiophene}4 (7) as a yellow oil. The 77Se NMR spectra
of 6 and 7 showed single resonances at 220.8 and 484.4 ppm,
respectively. The 1H NMR spectrum of 6 consists of a single reso-
nance at 3.96 ppm corresponding to the protons of methoxy
groups on thiophene rings. The reaction of 3-(hexyloxy)-4-meth-
oxythiophene with SeCl2 in THF/diethyl ether yielded a mixture
of compounds (8–11) containing possibly different types of struc-
tural isomers as evidenced by its 77Se NMR spectrum. All possible
structural isomers observed through the 77Se NMR spectrum are
depicted in Scheme 2. Attempts to separate these structural iso-
mers (8–11), using various separation techniques including col-
umn chromatography, have been unsuccessful.
The structure of selenacalix[4]thiophene (6) is determined by
single crystal X-ray analysis.17 The structure is shown in Figure 2
with bond parameters. The four 3,4-dimethoxy substituted thio-
phenes are linked by four selenium atoms bridging at 2,5 positions.
Due to the strong intermolecular interactions between Se1. . .O4
(3.030 Å) and Se2. . .C8 (3.367 Å) atoms, sidewise stacking of macro-
cycles was observed which resulted in two dimensional network.
The Se–C bond lengths are in the range of 1.897(5)–1.910(6) Å. The
C10–Se1–C1, C7–Se2–C4 bond angles are 98.1(2) and 99.4(2)°,
respectively. The diagonally located sulfur atoms S1. . .S1 are sepa-
rated by 5.6422(24) Å, while the distance between S2. . .S2 is
5.5447(24) Å. In the macrocycle four thienyl rings are not coplanar
6. (a) Hodage, A. S.; Phadnis, P. P.; Wadawale, A.; Priyadarsini, K. I.; Jain, V. K. Org.
Biomol. Chem. 2011, 9, 2992–2998; (b) Nascimento, V.; Alberto, E. E.; Tondo, D.
W.; Dambrowski, D.; Detty, M. R.; Nome, F.; Braga, A. L. J. Am. Chem. Soc. 2011,
134, 138–141.
7. Młochowski, J.; Kloc, K.; Syper, L.; Inglot, A. D.; Piasecki, E. Liebigs Ann. Chem.
1993, 1239–1244.
8. (a) Jen, K.-Y.; Benfaremo, N.; Cava, M. P.; Huang, W.-S.; MacDiarmid, A. G. J.
Chem. Soc., Chem. Commun. 1983, 633–634; (b) Mishra, S.; Jeanneau, E.; Daniele,
S. Polyhedron 2010, 29, 500–506; (c) Kumar, A.; Singh, J. D. Inorg. Chem. 2012,
51, 772–774.
9. (a) Klayman, D. L. Organic Selenium Compounds, Their Chemistry and Biology;
John Wiley: New York, NY, 1973; (b) Krief, A. Organoselenium Chemistry;
Springer: Berlin, 1988; (c) Mugesh, G.; Singh, H. B. Acc. Chem. Res. 2002, 35,
226–236; (d) Batchelor, R. J.; Einstein, F. W. B.; Gay, I. D.; Gu, J.-H.; Johnston, B.
D.; Pinto, B. M. J. Am. Chem. Soc. 1989, 111, 6582–6591.

P. Kumar et al. / Tetrahedron Letters 55 (2014) 5232–5235
5235
10. Amosova, S. V.; Penzik, M. V.; Albanov, A. I.; Potapov, V. A. Tetrahedron Lett.
2009, 50, 306–308.
15. Thomas, J.; Maes, W.; Robeyns, K.; Ovaere, M.; Meervelt, L. V.; Smet, M.;
Dehaen, W. Org. Lett. 2009, 11, 3040–3043.
11. Tsue, H.; Ishibashi, K.; Tamura, R. In Heterocyclic Supramolecules I, Topics in
Heterocyclic Chemistry; Matsumoto, K., Ed.; Springer: Heidelberg, 2008; Vol. 17,
pp 73–96.
12. (a) Niikura, K.; Anslyn, E. V. J. Chem. Soc., Perkin Trans. 2 1999, 2769–2775; (b)
Clayden, J.; Rowbottom, S. J. M.; Ebenezer, W. J.; Hutchings, M. G. Org. Biomol.
Chem. 2009, 7, 4871–4880; (c) Xue, M.; Chen, C.-F. Chem. Commun. 2011, 2318–
2320; (d) Tsue, H.; Takahashi, H.; Ishibashi, K.; Inoue, R.; Shimizu, S.;
Takahashi, D.; Tamura, R. Cryst. Eng. Comm. 2012, 14, 1021–1026; (e) Tsue,
H.; Ono, K.; Tokita, S.; Takahashi, H.; Tamura, R. Cryst. Eng. Comm. 2013, 15,
1536–1544.
13. (a) Katz, J. L.; Geller, B. J.; Foster, P. D. Chem. Commun. 2007, 1026–1028; (b)
Maes, W.; Dehaen, W. Chem. Soc. Rev. 2008, 37, 2393–2402; (c) Sobransingh, D.;
Dewal, M. B.; Hiller, J.; Smith, M. D.; Shimizu, L. S. New J. Chem. 2008, 32, 24–
27; (d) Hu, S.-Z.; Chen, C.-F. Chem. Commun. 2010, 4199–4201; (e) Yang, Y.;
Xue, M.; Chen, C.-F. Cryst. Eng. Comm. 2010, 12, 3502–3505; (f) Kleyn, A.;
Jacobs, T.; Barbour, L. J. Cryst. Eng. Comm. 2011, 13, 3175–3180; (g) Taylor, S.
M.; McIntosh, R. D.; Reze, J.; Dalgarno, S. J.; Brechin, E. K. Chem. Commun. 2012,
9263–9265.
14. (a) Lhoták, P. Eur. J. Org. Chem. 2004, 1675–1692; (b) Morohashi, N.; Narumi, F.;
Iki, N.; Hattori, T.; Miyano, S. Chem. Rev. 2006, 106, 5291–5316; (c) Kundrat, O.;
Eigner, V.; Dvorakova, H.; Lhoták, P. Org. Lett. 2011, 13, 4032–4035; (d)
Kundrat, O.; Dvorakova, H.; Cisarova, I.; Pojarova, M.; Lhoták, P. J. Org. Chem.
2010, 75, 407–411.
16. Thomas, J.; Rossom, W. V.; Hecke, K. V.; Meervelt, L. V.; Smet, M.; Maes, W.;
Dehaen, W. Chem. Commun. 2012, 43–45.
17. Crystal data for [(HOC10H6)2(
space group = P21/n, a = 8.3428(14), b = 8.1618(13), c = 22.261(4) Å,
b = 94.855(2)°,
= 90°, V = 1510.3(4) Å3, Z = 4, calcd = 1.606 g cmꢀ3
(MoK T = 100(2) K, 25383 reflections collected (h range
) = 2.493 mmꢀ1
2.54–29.11°), 3931 unique (Rint = 0.0303) with [I >2 (I)] and wR2 = 0.0795
(for all data). [(CH3OC10H6)2( -Se)] (2): C22H18O2Se, M = 393.32, orthorhombic,
space group = P21 P21 P21, a = 7.996(4), b = 10.860(5), c = 19.838(11) Å, = 90°,
b = 90, = 90°, Z = 4,
V = 1722.7(15) Å3, calcd = 1.516 g cmꢀ3
(MoK
) = 2.192 mmꢀ1, T = 100 K, 13131 reflections collected (h range 3.20–
25.40°), 3135 unique (Rint = 0.0680) with [I >2 (I)] and wR2 = 0.1033 (for all
data). {2,5-( -Se)(3,4-dimethoxythiophene)}4 (6): C24H24O8S4Se4, M = 884.51,
triclinic, space group = P-1, a = 7.6983(19) Å, b = 9.214(2) Å, c = 10.480(3) Å ,
l
-Se)] (1): C20H14O2Se, M = 365.27, monoclinic,
a
= 90°,
c
q
,
l
a
,
r
l
a
c
q
,
l
a
r
l
a
= 76.437(3)°,
c
= 82.884(3)°,
T = 100(2), 9856 reflections
(I)]
V = 717.1(3) Å3,
Z = 1,
q
calcd = 2.048 g cmꢀ3
) = 5.455 mmꢀ1
collected (h range 3.30 = 28.17°), 3149 unique (Rint = 0.0481) with [I >2
r
and wR2 = 0.1137 (for all data). CCDC 936464 (1), 977649 (2) and 936465 (6).
18. Kunnari, S. M.; Oilunkaniemi, R.; Laitinen, R. S.; Ahlgren, M. Acta Crystallogr.,
Sec. C 2002, 58, o610–o611.