Aromatic derivatives and tellurium analogues of cyclic seleninate esters and spirodioxyselenuranes that act as glutathione peroxidase mimetics

Article abstract of DOI:10.1021/jo0512711

Several novel organoselenium and tellurium compounds were prepared and evaluated as mimetics of the selenoenzyme glutathione peroxidase, which protects cells from oxidative stress by reducing harmful peroxides with the thiol glutathione. The compounds wer

Full text of DOI:10.1021/jo0512711

Aromatic Derivatives and Tellurium Analogues of Cyclic
Seleninate Esters and Spirodioxyselenuranes That Act as
Glutathione Peroxidase Mimetics
Thomas G. Back,* Dusˇan Kuzma, and Masood Parvez
Department of Chemistry, University of Calgary, Calgary, Alberta, Canada, T2N 1N4
tgback@ucalgary.ca
Received June 21, 2005
Several novel organoselenium and tellurium compounds were prepared and evaluated as mimetics
of the selenoenzyme glutathione peroxidase, which protects cells from oxidative stress by reducing
harmful peroxides with the thiol glutathione. The compounds were tested for catalytic activity in
a model system wherein tert-butyl hydroperoxide or hydrogen peroxide were reduced with benzyl
thiol and the rate of the reaction was measured by monitoring the formation of dibenzyl disulfide.
Thus, aromatic derivatives 19, 22, 24, and 25 proved to be inferior catalysts compared to the parent
cyclic seleninate ester 14 and spirodioxyselenurane 16. In the case of 19 and 22, this was the result
of their rapid conversion to the relatively inert selenenyl sulfides 31 and 32, respectively. In general,
hydrogen peroxide was reduced faster than tert-butyl hydroperoxide in the presence of the selenium-
based catalysts. The cyclic tellurinate ester 27 and spirodioxytellurane 29 proved to be superior
catalysts to their selenium analogues 14 and 16, respectively, resulting in the fastest reaction rates
by far of all of the compounds we have investigated to date. Oxidation of 29 with hydrogen peroxide
produced the unusual and unexpected peroxide 33, in which two hypervalent octahedral tellurium
moieties are joined by ether and peroxide bridges. The structure of 33 was confirmed by X-ray
crystallography. Although 33 displayed strong catalytic activity when tested independently in the
model system, its relatively slow formation from the oxidation of 29 rules out its intermediacy in
the catalytic cycle of 29.
Introduction
oxidative stress is mitigated by dietary antioxidants, as
well as by endogenous enzymes that catalyze the de-
struction of peroxides and other reactive oxygen species.1,3
The latter include glutathione peroxidase (GPx),4 which
promotes the reduction of peroxides with the stoichio-
metric reductant glutathione (GSH), a tripeptide thiol
that is ubiquitous in the cells of higher organisms. The
structure5 and catalytic mechanism4 of GPx have been
The formation of peroxide byproducts during the course
of normal aerobic metabolism contributes to oxidative
stress in living organisms.1 Peroxides, as well as free
radicals derived from them,2 have been implicated in a
variety of degenerative processes and diseases, including
inflammation, cardiovascular disease, mutagenesis and
cancer, dementia, and the aging process. Fortunately,
(3) Oxidative Processes and Antioxidants; Paoletti, R., Samuelsson,
B., Catapano, A. L., Poli, A., Rinetti, M., Eds.; Raven Press: New York,
1994.
(4) (a) Selenium in Biology and Human Health; Burk, R. F., Ed.;
Springer-Verlag: New York, 1994. (b) Ganther, H. E. Chem. Scr. 1975,
8a, 79. (c) Ganther, H. E.; Kraus, R. J. In Methods in Enzymology;
Colowick, S. P., Kaplan, N. O., Eds.; Academic Press: New York, 1984;
Vol. 107, pp 593-602. (d) Stadtman, T. C. J. Biol. Chem. 1991, 266,
16257. (e) Tappel, A. L. Curr. Top. Cell Regul. 1984, 24, 87. (f) Flohe´,
L. Curr. Top. Cell Regul. 1985, 27, 473.
* Corresponding author. Tel.: (403) 220-6256. Fax: (403) 289-9488.
(1) (a) Oxidative Stress; Sies, H., Ed; Academic Press: London, 1985.
(b) Free Radicals and Oxidative Stress: Environment, Drugs and Food
Additives; Rice-Evans, C., Halliwell, B., Lunt, G. G., Eds.; Portland
Press: London, 1995.
(2) (a) Free Radicals in Biology; Pryor, W. A., Ed.; Academic Press:
New York, 1976-1982; Vol. 1-5. (b) Free Radicals in Molecular
Biology, Aging and Disease; Armstrong, D., Sohal, R. S., Cutler, R. G.,
Slater, T. F., Eds.; Raven Press: New York, 1984.
10.1021/jo0512711 CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/12/2005
9230
J. Org. Chem. 2005, 70, 9230-9236

Glutathione Peroxidase Mimetics
SCHEME 1
CHART 1
extensively studied. The tetrameric enzyme contains a
selenocysteine residue in each of its four subunits, and
the catalytic activity of GPx results from the redox
properties of the selenocysteine selenol moieties. As
shown in Scheme 1, the selenol functionality (EnzSeH)
reacts with a peroxide molecule to generate the corre-
sponding selenenic acid (EnzSeOH). The latter then
reacts in succession with two molecules of glutathione
to regenerate the original selenol via the corresponding
selenenyl sulfide (EnzSeSG). Seleninic acid intermediates
(EnzSeO2H) have also been postulated at high peroxide
concentrations.
The design, synthesis, and evaluation of small-molecule
selenium compounds that mimic the biological activity
of GPx have been investigated by several groups,6 and
representative examples 1,7 2,8 3,9 4,10 5,11 6,12 7,13 8,14
9,15 and 1016 are shown in Chart 1. Ebselen (1) has
undergone clinical trials as an antioxidant.17 Certain
types of tellurium compounds (e.g. 1118 and 1219) as well
as dendrimeric20 and cyclodextrin-derived21 organochal-
cogen catalysts that emulate GPx have also been re-
ported. Several distinct mechanisms, including the one
in Scheme 1, have been identified in the catalytic cycles
of these mimetics. In general, substituents that are
capable of coordinating or covalently bonding with the
selenium or tellurium atom can be employed to modulate
the redox behavior and therefore the catalytic activity of
the compounds. While coordinating amino groups have
been widely studied for this purpose,22 oxygen substitu-
ents have been much less investigated.14,23 We recently
reported24 that the oxidation of allyl 3-hydroxypropyl
selenide (13) with tert-butyl hydroperoxide produces the
novel cyclic seleninate ester (14) rapidly and quantita-
tively by a series of oxidation and [2,3]sigmatropic
rearrangement steps. In the presence of a sacrificial thiol,
the latter then functions as an unusually effective
catalyst for the destruction of the peroxide via the
mechanism in Scheme 2. More recently, we demonstrated
that the similar oxidation of bis(3-hydroxypropyl) se-
lenide (15) produces the novel dialkoxyspiroselenurane
(16), which again displays exceptionally high catalytic
activity in this process via Scheme 3.25
(5) Epp, O.; Ladenstein, R.; Wendel, A. Eur. J. Biochem. 1983, 133,
51.
(6) For reviews, see: (a) Mugesh, G.; du Mont, W.-W.; Sies, H. Chem.
Rev. 2001, 101, 2125. (b) Mugesh, G.; Singh, H. B. Chem. Soc. Rev.
2000, 29, 347. (c) Mugesh, G.; du Mont, W.-W. Chem. Eur. J. 2001, 7,
1365.
(7) (a) Mu¨ller, A.; Cadenas, E.; Graf, P.; Sies, H. Biochem. Phar-
macol. 1984, 33, 3235. (b) Wendel, A.; Fausel, M.; Safayhi, H.; Tiegs,
G.; Otter, R. Biochem. Pharmacol. 1984, 33, 3241. (c) Parnham, M. J.;
Kindt, S. Biochem. Pharmacol. 1984, 33, 3247. (d) Mu¨ller, A.; Gabriel,
H.; Sies, H. Biochem. Pharmacol. 1985, 34, 1185. (e) Safayhi, H.; Tiegs,
G.; Wendel, A. Biochem. Pharmacol. 1985, 34, 2691. (f) Wendel, A.;
Tiegs, G. Biochem. Pharmacol. 1986, 35, 2115. (g) Fischer, H.; Dereu,
N. Bull. Soc. Chim. Belg. 1987, 96, 757. (h) Haenen, G. R. M. M.; De
Rooij, B. M.; Vermeulen, N. P. E.; Bast, A. Mol. Pharmacol. 1990, 37,
412. (i) Glass, R. S.; Farooqui, F.; Sabahi, M.; Ehler, K. W. J. Org.
Chem. 1989, 54, 1092.
(8) Reich, H. J.; Jasperse, C. P. J. Am. Chem. Soc. 1987, 109, 5549.
(9) (a) Erdelmeier, I.; Tailhan-Lomont, C.; Yadan, J.-C. J. Org.
Chem. 2000, 65, 8152. (b) Jacquemin, P. V.; Christiaens, L. E.; Renson,
M. J.; Evers, M. J.; Dereu, N. Tetrahedron Lett. 1992, 33, 3863.
(10) Wilson, S. R.; Zucker, P. A.; Huang, R.-R. C.; Spector, A. J. Am.
Chem. Soc. 1989, 111, 5936.
(11) Galet, V.; Bernier, J.-L.; He´nichart, J.-P.; Lesieur, D.; Abadie,
C.; Rochette, L.; Lindenbaum, A.; Chalas, J.; Renaud de la Faverie,
J.-F.; Pfeiffer, B.; Renard, P. J. Med. Chem. 1994, 37, 2903.
(12) Engman, L.; Andersson, C.; Morgenstern, R.; Cotgreave, I. A.;
Andersson, C. M.; Hallberg, A. Tetrahedron 1994, 50, 2929.
(13) Ostrovidov, S.; Franck, P.; Joseph, D.; Martarello, L.; Kirsch,
G.; Belleville, F.; Nabet, P.; Dousset, B. J. Med. Chem. 2000, 43, 1762.
(14) Wirth, T. Molecules 1998, 3, 164.
(15) (a) Mugesh, G.; Panda, A.; Singh, H. B.; Punekar, N. S.;
Butcher, R. J. J. Chem. Soc., Chem. Commun. 1998, 2227. For a related
investigation of ferrocenyl diselenides and congeners, see: (b) Kumar,
S.; Tripathi, S. K.; Singh, H. B.; Wolmersha¨user, G. J. Organomet.
Chem. 2004, 689, 3046.
(20) Drake, M. D.; Bright, F. V.; Detty, M. R. J. Am. Chem. Soc.
2003, 125, 12558.
(21) (a) Liu, Y.; Li, B.; Li, L.; Zhang, H.-Y. Helv. Chim. Acta 2002,
85, 9. (b) McNaughton, M.; Engman, L.; Birmingham, A.; Powis, G.;
Cotgreave, I. A. J. Med. Chem. 2004, 47, 233.
(22) For lead references, see: (a) Iwaoka, M.; Tomoda, S. J. Am.
Chem. Soc. 1994, 116, 2557. (b) Iwaoka, M.; Tomoda, S. J. Am. Chem.
Soc. 1996, 118, 8077. (c) Mugesh, G.; Panda, A.; Singh, H. B.; Punekar,
N. S.; Butcher, R. J. J. Am. Chem. Soc. 2001, 123, 839. (d) Mugesh,
G.; Panda, A.; Singh, H. B.; Butcher, R. J. Chem. Eur. J. 1999, 5, 1411.
(e) Mugesh, G.; Panda, A.; Kumar, S.; Apte, S. D.; Singh, H. B.;
Butcher, R. J. Organomet. 2002, 21, 884.
(16) Back, T. G.; Dyck, B. P. J. Am. Chem. Soc. 1997, 119, 2079.
(17) For a list of potential medicinal applications of ebselen, see:
Fong, M. C.; Schiesser, C. H. Tetrahedron Lett. 1995, 36, 7329 and
references therein.
(23) (a) Iwaoka, M.; Komatsu, H.; Katsuda, T.; Tomoda, S. J. Am.
Chem. Soc. 2004, 126, 5309. (b) Zade, S. S.; Panda, S.; Singh, H. B.;
Sunoj, R. B.; Butcher, R. J. J. Org. Chem. 2005, 70, 3693. (c) Zade, S.
S.; Singh, H. B.; Butcher, R. J. Angew. Chem., Int. Ed. 2004, 43, 4513.
(24) (a) Back, T. G.; Moussa, Z. J. Am. Chem. Soc. 2002, 124, 12104.
(b) Back, T. G.; Moussa, Z. J. Am. Chem. Soc. 2003, 125, 13455.
(25) Back, T. G.; Moussa, Z.; Parvez, M. Angew. Chem., Int. Ed.
2004, 43, 1268.
(18) You, Y.; Ahsan, K.; Detty, M. R. J. Am. Chem. Soc. 2003, 125,
4918.
(19) Kanda, T.; Engman, L.; Cotgreave, I. A.; Powis, G. J. Org. Chem.
1999, 64, 8161.
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Back et al.
SCHEME 2
SCHEME 4
SCHEME 3
To compare the catalytic activity of various GPx
mimetics, we have developed a convenient protocol based
on the reduction of tert-butyl hydroperoxide with benzyl
thiol (BnSH).16,24,25 This peroxide was chosen because it
is readily available and convenient to handle. The thiol
and its corresponding disulfide (BnSSBn) contain chro-
mophores that make their concentrations easy to monitor
by HPLC during the course of each reaction, while their
methylene groups provide convenient NMR signals for
further investigations of possible intermediates. The
assays were typically run with excess peroxide and 10
mol % of the catalyst in a mixture of dichloromethane-
methanol that was found to dissolve the peroxide, the
thiol, and a large variety of the catalysts that we
investigated. Assays were conducted at 18 °C in order to
facilitate monitoring some of the faster reactions, without
unduly retarding the slower ones. Since the kinetic
profiles of some of our earlier GPx mimetics were found
to include irregularities such as induction periods during
the initial oxidation step or unusually rapid early stage
kinetics (presumably due to the rapid conversion of the
catalyst to an intermediate that then reacts more slowly
in a subsequent step), we chose to compare the catalytic
activities of various GPx mimetics by means of half-lives
(t1/2), representing the time required to oxidize half of the
thiol to its disulfide. For example, when 90% tert-butyl
hydroperoxide was used under these conditions, 14 and
16 displayed t1/2 of 2.5 and 2.9 h, respectively, as
compared to 42 h for ebselen (1).24,25
hydroperoxide, to compare the reactivities of the two
oxidants. These new results, when taken in conjunction
with the previous studies of 14 and 16,24,25 provide new
insight into the structure-activity relationships of the
catalysts and their mechanisms.
Results and Discussion
The preparations of the cyclic seleninates 19 and 22,
as well as the spirodioxyselenuranes 24 and 25, are
shown in Scheme 4. With the exception of 25,26 these
compounds are novel, but all were easily obtained from
anthranilic acid via the known diselenide 1727 and
selenide 20.26 The novel tellurium compounds 27 and 29
were prepared as shown in Scheme 5.
The catalytic activities of the compounds investigated
are shown in Table 1, and kinetic plots are provided in
the Supporting Information. For comparison, control
experiments run in the absence of any selenium- or
tellurium-based catalyst produced t1/2 > 300 h with 90%
or 56% tert-butyl hydroperoxide and t1/2 ) 116 h with 29%
hydrogen peroxide. A reinvestigation of 14 with different
concentrations of tert-butyl hydroperoxide (entries 1-3),
as well as with hydrogen peroxide (entry 4), revealed that
its catalytic activity is highly dependent on the identity
and concentration of the oxidant. When the hydroperox-
ide was employed, a dramatic increase in t1/2 from 2.5 to
Since aliphatic organoselenium compounds tend to be
generally more toxic than aromatic analogues,6b we now
report an extension of our earlier investigation to aro-
matic congeners of 14 and 16, namely 19, 22, 24, and
25, as well as the novel tellurium analogues 27 and 29.
We also measured the catalytic activity of these com-
pounds with hydrogen peroxide in place of tert-butyl
(26) Dahle´n, B.; Lindgren, B. Acta Chem. Scand. 1973, 27, 2218.
(27) Lesser, R.; Weiss, R. Ber. Dtsch. Chem. Ges. 1913, 2640.
9232 J. Org. Chem., Vol. 70, No. 23, 2005

Glutathione Peroxidase Mimetics
TABLE 1. Catalytic Activities of GPx Mimeticsa
SCHEME 5
167 h was observed, as the concentration of the hydro-
peroxide reagent was changed from 90% to 38%. We also
noted that, as the hydroperoxide concentration was
lowered, an increasing accumulation of the corresponding
selenenyl sulfide 30 occurred (Scheme 6). The latter
compound had been previously identified as a minor
byproduct at high hydroperoxide concentrations, and it
was established that its formation comprises a competing
deactivation pathway because of its low catalytic activity
compared to that of the cyclic seleninate ester 14 itself.24
At low concentrations of the hydroperoxide, or in its
complete absence, 14 reacted with benzyl thiol to afford
30 quantitatively. By comparison, the t1/2 measured with
14 in the presence of 29% hydrogen peroxide was
considerably shorter than with a comparable concentra-
tion of the hydroperoxide (cf. entries 3 and 4).
Examination of the benzo analogue 19 revealed that
it displays lower catalytic activity than the parent
seleninate ester 14 with tert-butyl hydroperoxide (entry
2 vs 5) but identical activity in the reduction of hydrogen
peroxide (entry 4 vs 6). Introduction of the electron-
withdrawing carbonyl group in 22 decreased the catalytic
activity in the case of both tert-butyl hydroperoxide (entry
5 vs 7) and hydrogen peroxide (entry 6 vs 8), affording
t1/2 values only slightly shorter than control reactions run
in the absence of catalyst (vide supra). Further examina-
tion of the reactions catalyzed by 19 and 22 showed that
the two compounds were gradually converted into the
selenenyl sulfides 31 and 32, respectively, in the presence
of benzyl thiol and 56% tert-butyl hydroperoxide (entries
5 and 7, respectively). These compounds were isolated,
characterized, and assayed independently with 56% tert-
butyl hydroperoxide, revealing very poor catalytic activi-
ties (t1/2 ) 192 and >300 h, respectively). Similarly, the
reduction of 29% hydrogen peroxide with benzyl thiol in
the presence of 32 produced an unusually slow reaction
with t1/2 ) 89 h. It therefore appears that, as in the case
of 30 derived from 14, the formation of the corresponding
selenenyl sulfides 31 and 32 again comprises a deactiva-
tion pathway.
a Reactions were performed with BnSH (0.029 M), the catalyst
(0.0029 M), and either 56% TBHP (0.038 M), 38% TBHP (0.023
M), or 29% H2O2 (0.040 M) in CH2Cl2-MeOH (95:5) at 18 °C,
except for entries 7, 8, 17, and 18, where the solvent was CH2Cl2-
MeOH (4:1). b Data taken from ref 24. c Data taken from ref 25.
SCHEME 6
The spirodioxyselenurane 16 displayed lower sensitiv-
ity toward hydroperoxide concentration, affording strong
and comparable catalytic activity from 90% to 38% con-
centration (entries 9-11). Catalytic activity increased by
a further ca. 1 order of magnitude when hydrogen per-
oxide was employed as the oxidant. At the end of the cat-
alytic cycle, when the benzyl thiol had been consumed,
J. Org. Chem, Vol. 70, No. 23, 2005 9233

Back et al.
SCHEME 7
16 was the principal selenium-containing product present
in the mixture. On the other hand, when the reactions
were carried out in the presence of excess thiol, selenide
15 was recovered. This is consistent with the mechanism
shown in Scheme 3, although we cannot rule out that
the intermediate selenoxide catalyzes the reduction of the
hydroperoxide by an independent pathway when both the
hydroperoxide and thiol are present. The benzo analogue
24 showed much weaker catalytic activity (entry 13 and
14) than 16, while its benzoyl counterpart 25 proved to
be even more debilitated (entry 15 and 16) when em-
ployed with either oxidant.
We next investigated the novel tellurium analogues 27
and 29. These compounds afforded by far the strongest
catalytic activity of all of the GPx mimetics that we have
examined to date,16,24,25 with t1/2 values of <5 min, using
either 56% tert-butyl hydroperoxide (entry 17 and 19) or
29% hydrogen peroxide (entry 18 and 20). Although the
reactions catalyzed by 27 and 29 were too rapid to permit
a more detailed analysis of intermediates by NMR
techniques, control experiments indicated that 27 and
29 are inert to tert-butyl hydroperoxide for at least
several hours but that they react rapidly with benzyl
thiol. This is consistent with the mechanisms shown in
Schemes 2 and 3, where thiolysis, rather than oxidation
of the catalyst, provides entry into the catalytic cycle.
However, it is also possible that the corresponding
tellurenyl sulfide was produced during the catalytic cycle
of 27 but that, in contrast to its selenenyl sulfide
counterpart 30, it served as an efficient catalyst for the
reduction of the hydroperoxide. Unfortunately, the tel-
lurenyl sulfide proved relatively unstable and it was not
possible to isolate it in a pure state and measure its t1/2
in an independent experiment.
When the spirodioxytellurane 29 was treated with
excess 29% hydrogen peroxide in the absence of the thiol,
we unexpectedly obtained a new compound that was
isolated, characterized, and subjected to X-ray crystal-
lography (Scheme 7). It proved to have the highly
unusual peroxide structure 33, whose ORTEP diagram
is shown in Figure 1. The product is dimeric, where each
hypervalent tellurium atom occupies the center of a
distorted octahedron, bonded to four oxygen atoms in a
roughly square planar arrangement. The central ring
comprises a 1,2,4-trioxa-3,5-ditellurolane moiety that
includes the peroxide linkage. Full details of the crystal
structure are contained in the Supporting Information.
An independent assay of 33 indicated that it too has very
strong catalytic activity (t1/2 < 3 min with 29% hydrogen
peroxide or 56% tert-butyl hydroperoxide). However, its
FIGURE 1. ORTEP diagram of peroxide 33.
relatively slow formation from 29 via Scheme 7 (ca. 50%
complete after 6 h) indicates that it does not play a
significant role in the catalytic cycle of 29.
Conclusions
These experiments indicate that the benzo analogues
19 and 24 have diminished, or at best comparable,
catalytic activity relative to the original selenium-based
catalysts 14 and 16. The activity is further decreased
when electron-withdrawing carbonyl groups are intro-
duced in the benzoyl derivatives 22 and 25. Furthermore,
the diminished activity of 14 at low concentrations of tert-
butyl hydroperoxide, as well as the generally lower
catalytic activity of the benzo and benzoyl compounds 19
and 22, can be attributed to the formation of the
respective selenenyl sulfides 30-32. Thus, although
selenenyl sulfide intermediates have been postulated to
play a key role in the catalytic cycles of GPx (see Scheme
1) and of some of the mimetics reported earlier,6 their
formation in the present case represents a deactivation
pathway. This was unequivocally confirmed by the
measurement of their catalytic activities in independent
assays using authentic samples.
Our present results also indicate that the catalytic
reduction of hydrogen peroxide proceeds more rapidly by
up to an order of magnitude compared to that of tert-
butyl hydroperoxide when the selenium-containing cata-
lysts 14, 16, 19, 22, 24, and 25 are employed. Perhaps
most noteworthy of all is the observation that the novel
tellurium analogues 27 and 29 displayed remarkable
catalytic activity, affording t1/2 values in our model assay
of <5 min compared to 0.2-90 h for the corresponding
selenium analogues 14 and 16 under comparable condi-
tions of oxidant and concentration.
Finally, while spirodioxyselenurane 16 was stable
toward both oxidants in the absence of benzyl thiol, the
corresponding tellurane 29 was only resistant toward
tert-butyl hydroperoxide. When treated with hydrogen
peroxide, 29 was slowly converted into the unusual and
unexpected dimeric tellurium peroxide species 33. While
the latter displayed strong catalytic activity of its own
in an independent assay, its formation from 29 was too
slow for it to contribute significantly to the reduction of
hydrogen peroxide with benzyl thiol in the presence of
29.
9234 J. Org. Chem., Vol. 70, No. 23, 2005

Glutathione Peroxidase Mimetics
3.10 mmol) in 60 mL of dry THF. The stirred mixture was
cooled to 0 °C and 50 mL of absolute ethanol was added
dropwise. The mixture was warmed to room temperature and
after 15 min, 1.13 mL (12.4 mmol) of allyl iodide was added.
After 1 h, the mixture was acidified with 120 mL of 1 M HCl
and extracted with ether. The combined organic phases were
washed with water, dried, and concentrated in vacuo. The
residue was chromatographed (elution with 30% dichlo-
romethane-ethyl acetate) to give 998 mg (67%) of 21 as a white
solid: mp 137-138 °C (from benzene-petroleum ether); IR
(KBr) 3200-2300 (br), 1660 cm-1; 1H NMR (300 MHz) δ 8.16
(d, J ) 7.7 Hz, 1 H), 7.47-7.43 (m, 2 H), 7.29-7.23 (m, 1 H),
6.07-5.96 (m, 1 H), 5.39 (dd, J ) 16.9, 1.3 Hz, 1 H), 5.15 (d,
J ) 10.0 Hz, 1 H), 3.59 (d, J ) 7.2 Hz, 2 H); 13C NMR (75
MHz) δ 172.0, 139.3, 133.4, 133.3, 132.8, 128.3, 127.4, 124.9,
118.5, 28.4; mass spectrum, m/z (relative intensity) 242 (19,
M+), 201 (100); exact mass calcd for C10H10O280Se 241.9846,
found 241.9832. Anal. Calcd for C10H10O2Se: C, 49.81; H, 4.18.
Found: C, 49.72; H, 3.91.
These experiments further illustrate that diverse
mechanisms are possible in the reduction of peroxide
species with sacrificial thiols in the presence of small-
molecule organoselenium and tellurium compounds that
serve as catalysts for the process.
Experimental Section
Diselenide 17,27 selenide 20,26 and spirodioxyselenurane 2526
were prepared by literature procedures. Experimental details
for the preparation of 14 and 16 can be found in the Supporting
Information of refs 24 and 25, respectively. NMR spectra were
run in CDCl3 unless otherwise indicated. Chemical shifts for
77Se and 125Te NMR spectra are reported relative to dimethyl
selenide and dimethyl telluride, respectively (δ 0.00). The
spectra were recorded by using diphenyl diselenide in CDCl3
(δ 463 ppm28) or selenium dioxide in D2O (δ 1302.6 ppm29),
for 77Se NMR spectra, and diphenyl ditelluride in CDCl3 (δ
420.8 ppm30), for 125Te NMR spectra. Benzyl thiol was distilled
prior to use and the concentrations of tert-butyl hydroperoxide
and hydrogen peroxide were determined by iodometric analy-
sis.31
Benzo-3-oxo-1,2-Oxaselenolane Se-Oxide (22). tert-Butyl
hydroperoxide (0.65 mL of 56% aqueous solution, 3.8 mmol)
was added to 322 mg (1.33 mmol) of selenide 21 in 40 mL of
dichloromethane. The mixture was stirred at room tempera-
ture for 14 h, concentrated in vacuo, and recrystallized from
acetonitrile to provide 212 mg (74%) of 22 as a white solid with
Glassware used in the measurement of catalytic activity
(Table 1) was washed only with water followed by acetone,
and was flame-dried prior to use. Contamination with traces
of detergent or alkali produced abnormal kinetic results.
Allyl (2-Hydroxymethyl)phenyl Selenide (18). Disele-
nide 17 (1.43 g, 3.57 mmol) in 50 mL of dry THF was added
dropwise to a stirred solution of 0.69 g (18 mmol) of lithium
aluminum hydride in 20 mL of dry THF at 0 °C. After the
initial vigorous reaction subsided, the mixture was warmed
to room temperature, stirred for 6 h, and treated with 0.7 mL
(8 mmol) of allyl iodide. Stirring was continued overnight, the
mixture was quenched with 100 mL of water and filtered, and
the residue was washed thoroughly with ether. The filtrate
was extracted repeatedly with ether. The combined organic
layers were dried and concentrated in vacuo. The crude
product was chromatographed (elution with hexanes-ethyl
acetate 3:2) to afford 816 mg (50%) of 18 as a yellow oil: IR
mp 226-227 °C (from water): IR (KBr) 1653, 1583, 1276 cm-1
;
1H NMR (300 MHz, CD3OD) δ 8.23 (dd, J ) 7.7, 1.0 Hz, 1 H),
8.11 (dd, J ) 7.4, 1.3 Hz, 1 H), 7.85-7.80 (m, 1 H), 7.69-7.65
(m, 1 H); 13C NMR (100 MHz, D2O, 340 K) δ 170.8, 147.8,
134.8, 133.3, 131.6, 130.3, 125.1; 77Se NMR (57 MHz, DMSO-
d6) δ 1022.3; mass spectrum, m/z (relative intensity) 216 (9,
M+), 200 (28), 120 (100); exact mass calcd for C7H4O380Se
215.9326, found 215.9309.
Bis[2-(hydroxymethyl)phenyl] Selenide (23). Selenide
20 (360 mg, 1.12 mmol) in 15 mL of dry THF was added
dropwise to a refluxing solution of 128 mg (3.36 mmol) of
lithium aluminum hydride in 20 mL of dry THF under an
argon atmosphere. The resulting white slurry was refluxed
for an additional 90 min, cooled to room temperature, and
quenched cautiously with 50 mL of cold water. The mixture
was filtered, the residue was washed thoroughly with ether
and the filtrate was extracted repeatedly with ether. The
combined organic layers were washed with saturated NaCl and
water, dried, and concentrated in vacuo. The product was
chromatographed (elution with dichloromethane-ethyl acetate
3:1) to give 174 mg (53%) of 23 as a clear oil, which solidified
upon longer standing: mp 84-86 °C (from dichloromethane-
1
(neat) 3350 (br), 1028, 750 cm-1; H NMR (300 MHz) δ 7.54
(dd, J ) 7.4, 1.3 Hz, 1 H), 7.40 (dd, J ) 7.4, 1.3 Hz, 1 H), 7.31-
7.18 (m, 2 H), 6.00-5.86 (m, 1 H), 4.99-4.92 (m, 2 H), 4.76 (s,
2 H), 3.51 (d, J ) 7.7 Hz, 2 H), 2.40 (br s, 1 H); 13C NMR (75
MHz) δ 143.0, 134.8, 134.3, 129.7, 128.5, 128.4, 128.0, 117.3,
65.6, 31.1; mass spectrum, m/z (relative intensity) 228 (10, M+),
187 (38), 157 (17), 129 (26), 105 (17), 78 (100); exact mass calcd
for C10H12O80Se 228.0053, found 228.0060.
1
hexanes); IR (neat) 3300 (br), 1006, 733 cm-1; H NMR (300
Benzo-1,2-oxaselenolane Se-Oxide (19). tert-Butyl hy-
droperoxide (0.96 mL of 38% aqueous solution, 3.9 mmol) was
added to 448 mg (1.97 mmol) of selenide 18 in 15 mL of
dichloromethane. The mixture was stirred at room tempera-
ture overnight, concentrated in vacuo, and chromatographed
(elution with 20% methanol-ethyl acetate) to afford 351 mg
(88%) of 19 as a white solid: mp 139-140 °C (from ethyl
MHz) δ 7.47 (dd, J ) 6.9, 1.5 Hz, 1 H), 7.35-7.27 m, 2 H),
7.21-7.15 (m, 1 H), 4.77 (s, 2 H), 1.89 (br s, 1 H); 13C NMR
(75 MHz) δ 142.2, 134.6, 130.6, 129.0, 128.9, 128.5, 65.5; 77Se
NMR (76 MHz) δ 316.5; mass spectrum, m/z (relative intensity)
294 (40, M+), 292 (20), 246 (20), 228 (14), 195 (72), 91 (79), 77
(100); exact mass calcd for C14H14O280Se 294.0159, found
294.0139.
Spirodioxyselenurane (24). Selenide 23 (114 mg, 0.389
mmol) was dissolved in 15 mL of dichloromethane, and 80 µL
(0.7 mmol) of 29% aqueous hydrogen peroxide was added. The
mixture was stirred for 8 h at room temperature, the solvent
was evaporated, and the crude product was chromatographed
(elution with 75% ethyl acetate-hexanes) to afford 80 mg
(71%) of 24 as a white solid: mp 171-173 °C (from ethyl
acetate); IR (KBr) 2798, 1441, 1201, 1008 cm-1; 1H NMR (300
MHz) δ 8.03 (d, J ) 7.2 Hz, 1 H), 7.41-7.34 (m, 2 H), 7.26-
7.23 (m, 1 H), 5.32 (s, 2 H); 13C NMR (75 MHz) δ 143.8, 134.1,
131.1, 128.2, 127.9, 124.3, 71.0; 77Se NMR (76 MHz) δ 804.4;
mass spectrum, m/z (relative intensity) 292 (20, M+), 291 (47),
263 (68), 77 (100). Anal. Calcd for C14H12O2Se: C, 57.74; H,
4.15. Found: C, 57.57; H, 4.18.
1
acetate); IR (KBr) 1462, 1260, 966 cm-1; H NMR (300 MHz)
δ 7.81 (d, J ) 7.7 Hz, 1 H), 7.61-7.47 (m, 3 H), 5.97 (d, J )
13.8 Hz, 1 H), 5.61 (d, J ) 13.6 Hz, 1 H); 13C NMR (75 MHz)
δ 148.3, 143.7, 132.2, 129.3, 125.5, 122.9, 78.6; 77Se NMR (76
MHz) δ 1349.1; mass spectrum, m/z (relative intensity) 202
(30, M+), 106 (74), 78 (100); exact mass calcd for C7H6O280Se
201.9533, found 201.9540. Anal. Calcd for C7H6O2Se: C, 41.81;
H, 3.01. Found: C, 41.54; H 2.97.
Allyl 2-Carboxyphenyl Selenide (21). Sodium borohy-
dride (0.59 g, 16 mmol) was added to diselenide 17 (1.24 g,
(28) Duddeck, H. Progr. NMR Spectrosc. 1995, 27, 1.
(29) Pekonen, P.; Hiltunen, Y.; Laitinen, R. S.; Pakkanen, T. A.
Inorg. Chem. 1990, 29, 2770.
(30) Granger, P.; Chapelle, S.; McWhinnie, W. R.; Al-Rubaie, A. J.
Organomet. Chem 1981, 220, 149.
Spirodioxyselenurane (25). The product was obtained in
73% yield by oxidation of selenide 20 with hydrogen peroxide
as described in the literature:26 mp 326-328 °C (from ethyl
(31) Wagner, C. D.; Smith, R. H.; Peters, E. D. Anal. Chem. 1947,
19, 976.
J. Org. Chem, Vol. 70, No. 23, 2005 9235

Back et al.
1
acetate) (lit.26 mp 310-322 °C); IR (KBr) 1695, 1269, 1104,
831, 743 cm-1 1H NMR (300 MHz,) δ 8.25-8.10 (m, 4 H),
a waxy solid: IR (neat) 1137, 1040, 982 cm-1; H NMR (300
MHz) δ 4.25-4.18 (m, 2 H), 3.79-3.72 (m, 2 H), 2.90-2.73
(m, 4 H), 2.30-2.12 (m, 2 H), 1.95-1.73 (m, 2 H); 13C NMR
(75 MHz) δ 67.4, 28.5, 27.2; 125Te NMR (126 MHz) δ 1095.8;
mass spectrum, m/z (relative intensity) 246 (1, M+), 188 (42),
130 (39), 43 (56); exact mass calcd for C6H12O2130Te 245.9900,
found 245.9911. Anal. Calcd for C6H12O2Te: C, 29.56; H, 4.96.
Found: C, 29.42; H, 5.05.
;
7.90-7.75 (m, 4 H); 13C NMR (75 MHz, DMSO-d6) δ 169.8,
142.7, 136.2, 133.9, 130.4, 130.2, 127.1. Anal. Calcd for
C14H8O4Se: C, 52.68; H, 2.53. Found: C, 52.25; H 2.43.
Bis(3-hydroxypropyl) Ditelluride (26). Water (30 mL)
was added dropwise to 2.08 g (16.3 mmol) of tellurium powder
and 0.62 g (16 mmol) of sodium borohydride under argon. The
mixture was heated until the tellurium dissolved to afford a
dark red solution. After it was cooled to room temperature,
2.27 g (16.3 mmol) of 3-bromo-1-propanol and 5 mL of water
were added. The solution turned orange and was stirred for
an additional 3 h. The mixture was extracted with ether, and
the combined organic phases were dried, concentrated in
vacuo, and chromatographed (elution with 60% ethyl acetate-
hexanes) to give 1.14 g (37%) of 26 as a viscous red oil: IR
(neat) 3230, 1201 cm-1; 1H NMR (300 MHz) δ 3.71 (t, J ) 6.1
Hz, 4 H), 3.20 (t, J ) 7.2 Hz, 4 H), 2.08-1.98 (m, 4 H), 1.86
(br s, 2 H); 13C NMR (75 MHz) δ 63.6, 36.1, -0.2; 125Te NMR
(95 MHz) δ 120.0; mass spectrum, m/z (relative intensity) 378
(1, M+), 256 (10), 171 (14), 130 (49), 39 (100). The deposition
of tellurium from the product was observed within a few days
even when the product was stored in a refrigerator. It was
used without further purification.
Selenenyl Sulfide 31. Cyclic seleninate ester 19 (115 mg,
0.572 mmol) was dissolved in 40 mL of dichloromethane and
cooled in an ice bath. Benzyl thiol (202 µL, 1.72 mmol) was
added and stirring was continued for 10 min. The solution
turned dark violet and then yellow. The solvent was evapo-
rated and the crude product was chromatographed (elution
with 15% ethyl acetate-hexanes) to afford 153 mg (86%) of
31 as a pale yellow oil, which was stored in the refrigerator:
IR (neat) 3356, 1258, 1198, 1023, 755, 695 cm-1; 1H NMR (300
MHz) δ 7.75 (d, J ) 6.7 Hz, 1 H), 7.37-7.12 (m, 8 H), 4.77 (s,
2 H), 4.04 (s, 2 H), 1.96 (s, 1 H); 13C NMR (75 MHz) δ 140.9,
137.8, 132.2, 131.8, 129.3, 128.7, 128.6, 128.5, 128.0, 127.6,
65.5, 42.3; 77Se NMR (76 MHz) δ 440.2; mass spectrum, m/z
(relative intensity) 310 (8, M+), 186 (18), 91 (100), exact mass
calcd for C14H14OS80Se 309.9931, found 309.9954. Anal. Calcd
for C14H14OSSe: C, 54.37; H, 4.56. Found: C, 54.58; H, 4.81.
1,2-Oxatellurolane Te-Oxide (27). tert-Butyl hydroper-
oxide (750 µL of 56% solution, 4.5 mmol) was added to
ditelluride 26 (241 mg, 0.646 mmol) in 35 mL of dichlo-
romethane. The color of the ditelluride was discharged within
5 min. After an additional 30 min, the solution was concen-
trated in vacuo and the product was precipitated from metha-
nol to afford 151 mg (58%) of 27 as a white solid: mp 257-
260 °C; IR (KBr) 1033, 979, 664 cm-1; 1H NMR (300 MHz, D2O)
δ 4.23 (t, J ) 5.3 Hz, 2 H), 3.11 (t, J ) 6.7 Hz, 2 H), 2.21-2.16
(m, 2 H); 13C NMR (100 MHz, D2O) δ 70.2, 46.9, 27.6; 125Te
NMR (95 MHz, D2O) δ 1042.0; mass spectrum, m/z (relative
intensity); mass spectrum, m/z (relative intensity) 204 (5, M+),
188 (66), 130 (100); exact mass calcd for C3H6O2130Te 203.9430,
found 203.9418. Anal. Calcd for C3H6O2Te: C, 17.87; H, 3.00.
Found: C, 18.19; H, 2.95.
Selenenyl Sulfide 32. Cyclic seleninate ester 22 (22 mg,
0.10 mmol) was dissolved in 10 mL of methanol. Benzyl thiol
(32 µL, 0.27 mmol) was added and the mixture was stirred
for 1 h at room temperature. The product was concentrated
in vacuo and recrystallized from ethyl acetate-hexanes to
afford 23 mg (73%) of 32 as a white solid: mp 153-155 °C; IR
1
(KBr) 3300-2300, 1660, 1266, 1027, 736 cm-1; H NMR (300
MHz) δ 8.19-8.10 (m, 2 H), 7.52-7.46 (m, 1 H), 7.47-7.18
(m, 6 H), 4.04 (s, 2 H); 13C NMR (75 MHz) δ 172.2, 139.0, 138.2,
134.0, 132.6, 129.1, 128.7, 127.6, 126.3, 125.9, 42.3; 77Se NMR
(57 MHz) δ 566.8; mass spectrum, m/z (relative intensity) 324
(2, M+), 200 (7), 91 (100). Anal. Calcd for C14H12O2SSe: C,
52.02; H, 3.74. Found: C, 51.86; H, 3.74.
Peroxide 33. Bis(3-hydroxypropyl) telluride 28 (170 mg,
0.693 mmol) was dissolved in 15 mL of dichloromethane and
treated with hydrogen peroxide (150 µL of 29% solution, 1.4
mmol). The mixture turned clear within ca. 1 min and was
then stirred for an additional 16 h at room temperature. The
product was concentrated in vacuo to give 185 mg (100%) of a
solid, which was recrystallized from ethanol to afford 126 mg
(68%) of 33: mp 211-213 °C; IR (KBr) 1221, 1044, 989, 810
Bis(3-hydroxypropyl) Telluride (28). Hydroxymethane-
sulfinic acid monosodium salt dihydrate (3.0 g, 19 mmol) was
added to 0.50 g (3.9 mmol) of tellurium powder and 2.5 g (63
mmol) of sodium hydroxide in 30 mL of water. The dark red
mixture was refluxed under argon until it formed a pale pink
solution (ca. 30 min). The solution was cooled to room tem-
perature and 0.69 mL (7.6 mmol) of 3-bromo-1-propanol was
added. The mixture turned yellow within 5 min and was
stirred for an additional 30 min. The product was extracted
with ether, dried, concentrated in vacuo, and chromatographed
(elution with ethyl acetate) to give 0.51 g (55%) of 28 as a
cm-1 1H NMR (300 MHz) δ 4.20-4.08 (m, 2 H), 4.08-3.95
;
(m, 4 H), 3.84-3.70 (m, 2 H), 2.95-2.70 (m, 4 H), 2.68-2.53
(m, 2 H), 2.45-2.16 (m, 8 H), 2.16-1.95 (m, 2 H); 13C NMR
(75 MHz) δ 61.2, 60.8, 37.9, 35.1, 24.7, 24.5; 125Te NMR (126
MHz) δ 1123.7. Anal. Calcd for C12H24O7Te2: C, 26.91; H, 4.52.
Found: C, 27.04; H, 4.37. For the X-ray crystal structure of
the product, see Figure 1 and the Supporting Information.
1
yellow oil: IR (neat) 3340, 1221 cm-1; H NMR (300 MHz) δ
3.72 (t, J ) 6.0 Hz, 4 H), 2.74 (t, J ) 7.4 Hz, 4 H), 2.07-1.98
(m, 4 H), 1.80 (br s, 2 H); 13C NMR (75 MHz) δ 64.0, 34.7,
-1.4; 125Te NMR (95 MHz) δ 229.5; mass spectrum, m/z
(relative intensity) 248 (53, M+), 189 (20), 172 (53), 130 (26),
57 (56), 41 (100); exact mass calcd for C6H14O2130Te 248.0056,
found 248.0044. The air-sensitive product was used directly
without further purification.
Acknowledgment. We thank the Natural Sciences
and Engineering Research Council of Canada for finan-
cial support.
Spirodioxytellurane (29). tert-Butyl hydroperoxide (550
µL of 38% solution, 2.2 mmol) was added to 524 mg (2.13
mmol) of telluride 28 in 15 mL of dichloromethane. The yellow
mixture turned colorless and clear within 5 min and was
stirred at room temperature for an additional 30 min. The
solvent was evaporated under vacuum to give a colorless oil,
which solidified upon standing to give 489 mg (94%) of 29 as
Supporting Information Available: 1H, 13C, 77Se, and
125Te NMR spectra, kinetic plots for the results summarized
in Table 1, and X-ray crystallographic data for peroxide 33.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO0512711
9236 J. Org. Chem., Vol. 70, No. 23, 2005