The unexpected formation of a triselenide from 4-methyl-5-tri-n-butylstannyl-1,3-dithiol-2-one and selenium dioxide

Article abstract of DOI:10.1016/j.inoche.2017.02.005

When attempting to apply a Riley oxidation to a stannylated precursor instead of the expected aldehyde an acyclic triselenide was obtained in which a Se₃ chain replaces the ⁿBu₃Sn substituents of two precursors. The reaction was found to be fully reproducible. The product bearing the Se₃ moiety and, hence, potentially possessing beneficial biological activity was analyzed comprehensively including X-ray structural characterization and ⁷⁷Se NMR.

Full text of DOI:10.1016/j.inoche.2017.02.005

Accepted Manuscript
The unexpected formation of a triselenide from 4-methyl-5-tri-n-
butylstannyl-1,3-dithiol-2-one and selenium dioxide
Claudia Schindler, Carola Schulzke
PII:
S1387-7003(16)30566-4
doi: 10.1016/j.inoche.2017.02.005
INOCHE 6554
DOI:
Reference:
To appear in:
Inorganic Chemistry Communications
Received date:
Revised date:
Accepted date:
15 December 2016
4 February 2017
13 February 2017
Please cite this article as: Claudia Schindler, Carola Schulzke , The unexpected formation
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ACCEPTED MANUSCRIPT
The unexpected formation of a triselenide from 4-methyl-5-tri-n-butylstannyl-1,3-
dithiol-2-one and selenium dioxide
1
1
Claudia Schindler , Carola Schulzke *
1
Ernst-Moritz-Arndt-Universität Greifswald; Institut für Biochemie,
Felix-Hausdorff-Straße 4, 17487 Greifswald, Germany
е-mail: carola.schulzke@uni-greifswald.de
Abstract: When attempting to apply a Riley oxidation to a stannylated precursor instead of
the expected aldehyde an acyclic triselenide was obtained in which a Se chain replaces the
3
n
Bu Sn substituents of two precursors. The reaction was found to be fully reproducible. The
3
product bearing the Se moiety and, hence, potentially possessing beneficial biological
3
7
7
activity was analyzed comprehensively including X-ray structural characterization and Se-
NMR.
Keywords: Triselenides, Riley Oxidation, Selenium Dioxide, Stannylation, Catenation
In course of a multistep dithiolene ligand synthesis a number of reactants, some of which
bearing inorganic main group elements or metals, were employed. For a particular series of
reactions the order of transformations was anticipated to be critical. Eventually it was decided
to attempt a SeO mediated Riley oxidation after stannylation of the ligand’s backbone.
2
Surprisingly, instead of the desired product this order of reactions yielded a novel triselenide
in which the three chalcogens O, S and Se account for more than half of all non-hydrogen
atoms present.
[
1]
The first triselenide bearing organic substituents was reported in 1929. In recent years the
interest in exploring the chemistry of selenium-containing compounds has increased due to
[
2]
their biological and medicinal importance. Selenium is an essential element in the active
sites of several enzymes as for instance glutathione peroxidase, the main biological role of
which is to protect the organism from oxidative damage by catalyzing the reduction of
[
3]
reactive oxygen species (ROS), and thioredoxin reductase playing an important role for
many aspects of cell function; e.g. protection against oxidative damage and the recycling of
ascorbate from its oxidized form. The availability of selenium is a key factor determining
[
4]
inter allia thioredoxin reductase activity both in cell culture and in vivo. The development
and investigation of low to medium molecular weight compounds bearing biologically active
selenium are, hence, of considerable interest. Here we report the (initially unexpected)
synthesis, analytical and structural characterisation of bis[4-methyl-1,3-dithiol-2-one]
triselenide via an unprecedented route.
1
-Bromopropan-2-one 1 was synthesized from acetone according to a slightly modified
literature procedure (acetic acid was added to the reaction mixture after the needed
[
5]
temperature was reached instead of heating together with acetic acid; Scheme 1). At r.t. and
in air 1 started to decompose almost immediately to a brown colored oil. For this instability, it
is requisite to continue with any following reaction steps without pause. Compound 1 was
converted to the corresponding xanthate directly after its preparation. The reactant potassium-
O-isopropylxanthate was obtained from the corresponding alcohol by reaction with KOH and
[6]
CS2. The ring-closing step leading to the formation of the 1,3-dithiol-2-one system is an

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acid-catalyzed cyclization, called Chugaev elimination. The highest yield was obtained
utilizing concentrated sulfuric acid. Washing with water, extraction with diethyl ether and
subsequent drying yields the pure heterocyclic product 3.
O
O
O
Br2
O-isopropylxanthate
S
O
CH3
Br
rt
H C
3
H C
CH3
3
H C
3
1
2
S
CH3
H SO
2
4
O
O
rt
S
S
S
S
O
H C
H C
3
3
SeO2
SnCl(nBu)3
Sn
Sn
S
1
02°C, dioxane
CH3
S
O
LDA -78°C
5
CH3
4
3
CH3
H C
CH3 H C
3
3
O
S
SeO2
dioxane
102°C
S
Se Se
Se
S
CH3
H C
3
6
S
O
Scheme 1. Synthesis of triselenide 6.
Treatment of a pre-mixed THF solution of 3 and tributyltin chloride at –78 °C with freshly
[7]
prepared LDA gave the tin compound 4. The transformation of the methylgroup of 4 to the
aldehyde 5 was the original aim of this study. Selenium dioxide is frequently used for
selectively and mildly oxidizing activated methyl and methylenes moieties into aldehydes and
ketone respectively, in a so called Riley oxidation. A particular advantage of employing SeO2
as an oxidizing agent is avoiding subsequent further oxidation of aldehydes to the
[
8]
corresponding carboxylic acids.
4-Methyl-5-tri-n-butylstannyl-1,3-dithiol-2-one 4 was
refluxed with freshly prepared selenium dioxide in freshly purified dioxane under nitrogen
[
9]
atmosphere. Instead of the expected product 5, however, triselenide 6 was formed.
Repetitions of the reaction led again to the formation of novel triselenide 6, which was
supported by several analytical methods including single crystal X-ray diffraction (see Figure
7
7
1
) and Se NMR spectroscopy. For complete experimental synthetic and analytical details
please refer to the SI. Compound 6 is soluble in a broad range of organic solvents of different
polarity (CHCl to CH CN) and stable in air even in solution. To the best of our knowledge,
3
3
SeO has not been reported previously as reagent for the generation of triselenides.
2
The molecular structure of compound 6 was determined by single X-ray crystallography. 6
crystallizes from acetone in the orthorhombic space group P2 2 2. The values for the Se(1)-Se
1
1
bond distance of 2.3586(12) Å, the Se(1)-C(2) bond distance of 1.914(10) Å, and the Se(1)-
Se(2)-Se(1A) angle of 106.49(7)° are comparable with previously reported values ranging
[
10]
from 1.86 to 2.013 Å, from 2.211 to 2.358 Å and from 99.68 to 112.59° respectively. The
C-Se bond here, notably, is the second shortest distance of all reported to date (only in CN-
[10a]
Se -CN is it shorter ). The Se-Se bond in contrast matches the highest value reported so far.
3

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Figure 1. Molecular Structure of 6. Relevant Bond Lengths (Å) and Angles (deg): Se(1)-C(2)
1
.914(10), Se(1)-Se(2) 2.3586(12); C(2)-Se(1)-Se(2) 99.2(3); Se(1)-Se(2)-Se(1)#1 106.49(7)
This indicates that the Se-C bond is affected by the C-C -bond of the dithiolene moiety
binding selenium whereas the Se-Se bond lengths are consistent with pure single -bonds.
The geometry around the central Se atom is V-shaped, with the Se-Se-Se angle falling right
into the middle of the reported range. While the angle is unexceptional, the bond lengths
suggest that a delocalization of electron density from the dithiolene moiety towards the
substituent on the C=C double bond takes place. This unusual ligand precursor after
deprotection and metal binding would, hence, constitute a particularly strongly non-innocent
ligand and it can be expected that the triselenide is dismembered upon complexation. This
novel compound promises therefore to constitute a quite efficient selenium delivery system,
which will be subject of further investigation
7
7
The Se NMR spectrum of the pure triselenide 6 shows two signals at 444 ppm and 479 ppm,
7
7
arising from the carbon bound and the central selenium atoms respectively. The Se chemical
7
7
shifts are not very different from Se-NMR data of previously reported triselenides in a range
[10m, 11]
of 330 to 651 ppm.
They are, however, on the highfield end of this range, suggesting
that the substituents on the Se moiety are comparably strong shielders. In this context it is
3
surprising that both types of selenium atoms appear to be more or less equally shielded. The
separation of the two signals here is comparably small with 35 ppm. Only with the very bulky
and sterically restricted thiophen-tripticyl substituent on both ends of the Se moiety a smaller
3
[
11b]
separation of only 9 ppm (549 and 558 ppm) was found.
The largest observed separation
of 295 ppm (330 and 625 ppm) is most likely caused by the interaction of ring nitrogen atoms
of the oxazine-phenyl substituents with the carbon bound selenium atoms leading to a
[
10m]
significant highfield shift of the respective signal due to strongly increased shielding.
Typical separation values for triselenides with more ordinary substituents were reported at
[
11a, 11c]
around 80-90 ppm.
The chemical shifts in this work were referenced according to the
[
12]
IUPAC recommendation verified with SeO in D O.
2
2
In conclusion, a new and reproducible procedure for the synthesis of triselenide compounds
n
using selenium dioxide was found. As this constitutes a substitution of a Sn Bu substituent it
3
is quite likely that this method can be applied to a variety of respective different precursors.
Structural characterization by single crystal X-ray diffraction studies suggests a particularly
strong non-innocence of the dithiolene and, hence, potential as selenium donor reagent of the
7
7
triselenide. Se NMR data of Bis[4-methyl-1,3-dithiol-2-one] triselenide 6 are falling into the
typical range with a noticeable small separation of the two (C-Se-Se and Se-Se-Se) observed
shifts.

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Acknowledgments.
7
7
We thank Dipl.-Chem. G. Thede for numerous solution NMR measurements and Se NMR
measurement in particular. Generous financial support from the European Research Council
(project MocoModels) is gratefully acknowledged.
References.
[
1]
G. R. Levi, A. Baroni, Atti Accad. Naz. Lincei, Cl. Sci. Fis., Mat. Nat., Rend. 1929, 9,
019-1024.
a) E. Mangiapane, A. Pessione, E. Pessione, Current Protein & Peptide Science 2014,
5, 598-607; b) J. K. Wrobel, R. Power, M. Toborek, IUBMB Life 2016, 68, 97-105;
1
[
2]
1
c) J. Aaseth, J. Alexander, G. Bjørklund, K. Hestad, P. Dusek, P. M. Roos, U.
Alehagen, BioMetals 2016, 29, 827-839.
[
[
3]
4]
a) K. Takahashi, N. Avissar, J. Whitin, H. Cohen, Arch. Biochem. Biophys. 1987, 256,
6
2
77-686; b) F. F. Chu, J. H. Doroshow, R. S. Esworthy, J. Biol. Chem. 1993, 268,
571-2576.
a) S.-R. Lee, J.-R. Kim, K.-S. Kwon, H. W. Yoon, R. L. Levine, A. Ginsburg, S. G.
Rhee, J. Biol. Chem. 1999, 274, 4722-4734; b) A. Lescure, D. Gautheret, P. Carbon,
A. Krol, J. Biol. Chem. 1999, 274, 38147-38154; c) D. Mustacich, G. Powis, Biochem.
J. 2000, 346, 1-8; d) S. Watabe, Y. Makino, K. Ogawa, T. Hiroi, Y. Yamamoto, S. Y.
Takahashi, Eur. J. Biochem. 1999, 264, 74-84; e) C. H. Williams, Jr., L. D. Arscott, S.
Muller, B. W. Lennon, M. L. Ludwig, P.-F. Wang, D. M. Veine, K. Becker, R. H.
Schirmer, Eur. J. Biochem. 2000, 267, 6110-6117.
[
[
[
[
[
5]
6]
7]
8]
9]
J. McNulty, C. Zepeda-Velazquez, Angew. Chem., Int. Ed. 2014, 53, 8450-8454.
V. Madhu, S. K. Das, Inorg. Chem. 2008, 47, 5055-5070.
A. Dinsmore, C. David Garner, J. A. Joule, Tetrahedron 1998, 54, 3291-3302.
H. L. Riley, J. F. Morley, N. A. C. Friend, J. Chem. Soc. 1932, 1875-1883.
A. Dinsmore, P. Ikhide, D. G. Billing, M. A. Fernandes, F. Marsicano, L. Selemela,
Inorg. Chem. Commun. 2005, 8, 293-296.
[
10] a) C. J. Burchell, P. Kilian, A. M. Z. Slawin, J. D. Woollins, K. Tersago, C. Van
Alsenoy, F. Blockhuys, Inorg. Chem. 2006, 45, 710-716; b) A. Ilie, A. Soran, A.
Laguna, C. Silvestru, Acta Crystallographica Section E 2011, 67, o1908; c) P. G.
Jones, J. Jeske, CSD, DOI: 10.5517/cc80fym, 2004; d) B. D. Rekken, T. M. Brown, J.
C. Fettinger, F. Lips, H. M. Tuononen, R. H. Herber, P. P. Power, J. Am. Chem. Soc.
2
013, 135, 10134-10148; e) M. Kulcsar, A. Silvestru, F. Cziple, Acta
Crystallographica Section C 2007, 63, o701-o703; f) S. Takahiro, M. Eiko, T.
Norihiro, Bull. Chem. Soc. Jpn. 2007, 80, 2425-2435; g) T. M. Klapötke, B. Krumm,
K. Polborn, Z. Anorg. Allg. Chem. 2008, 634, 1287-1290; h) C. Thone, F. Vancea, P.
G. Jones CSD, DOI: 10.5517/cctqkbd, 2010; i) T. M. Klapötke, B. Krumm, M. Scherr,
Acta Crystallographica Section E 2007, 63, o1965-o1966; j) A. Arnold, K. Cavell, A.
Edwards, B. Hoskins, E. Peacock, Aust. J. Chem. 1988, 41, 1601-1606; k) T. M.
Klapötke, B. Krumm, K. Polborn, M. Scherr, Eur. J. Inorg. Chem. 2006, 2006, 2937-
2
1
941; l) P. K. Atanassov, A. Linden, H. Heimgartner, Helv. Chim. Acta 2004, 87,
873-1887; m) S. Kumar, K. Kandasamy, H. B. Singh, G. Wolmershäuser, R. J.
Butcher, Organometallics 2004, 23, 4199-4208.
[
[
11] a) C. M. Bates, C. P. Morley, J. Organomet. Chem. 1997, 533, 193-196; b) A. Ishii, S.
Matsubayashi, T. Takahashi, J. Nakayama, J. Org. Chem. 1999, 64, 1084-1085; c) F.
Sladky, B. Bildstein, C. Rieker, A. Gieren, H. Betz, T. Hubner, J. Chem. Soc., Chem.
Commun. 1985, 1800-1801.
12] R. K. Harris, E. D. Becker, S. M. Cabral De Menezes, P. Granger, R. E. Hoffman, K.
W. Zilm, Pure Appl. Chem. 2008, 80, 59-84.

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Graphical abstract

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Highlights:



A novel pathway toward symmetrically substituted triselenides was discovered.
A novel triselenide was synthesized.7
7
Pecularities of crystallographic and Se-NMR data of the novel compound are being
discussed.