Effects of methoxy substituents on the glutathione peroxidase-like activity of cyclic seleninate esters

Article abstract of DOI:10.1021/jo501689h

Cyclic seleninate esters function as mimetics of the antioxidant enzyme glutathione peroxidase and catalyze the reduction of hydrogen peroxide with a stoichiometric thiol. While a single electron-donating methoxy substituent para to the selenium atom enhances the catalytic activity, m-methoxy groups have little effect and o-methoxy substituents suppress activity. The effects of multiple methoxy groups are not cumulative. This behavior can be rationalized by opposing mesomeric and steric effects. Oxidation of the product disulfide via its thiolsulfinate was also observed.

Full text of DOI:10.1021/jo501689h

Note
pubs.acs.org/joc
Effects of Methoxy Substituents on the Glutathione Peroxidase-like
Activity of Cyclic Seleninate Esters
David J. Press, Nicole M. R. McNeil, Miranda Hambrook, and Thomas G. Back*
Department of Chemistry, University of Calgary, 2500 University Drive NW, Calgary, Alberta, Canada T2N 1N4
S
* Supporting Information
ABSTRACT: Cyclic seleninate esters function as mimetics of
the antioxidant enzyme glutathione peroxidase and catalyze the
reduction of hydrogen peroxide with a stoichiometric thiol.
While a single electron-donating methoxy substituent para to
the selenium atom enhances the catalytic activity, m-methoxy
groups have little effect and o-methoxy substituents suppress
activity. The effects of multiple methoxy groups are not
cumulative. This behavior can be rationalized by opposing
mesomeric and steric effects. Oxidation of the product disulfide via its thiolsulfinate was also observed.
lutathione peroxidase (GPx)1,2 plays a vital antioxidant
role in human physiology. It consists of a family of seven
Scheme 1
G
isozymes, five of which contain the element selenium in the
form of selenocysteine residues.3 The structure of bovine
erythrocyte GPx was first elucidated by Epp, Ladenstein, and
Wendel,4 who established that it consists of a homotetrameric
structure, in which each of the four subunits contains a redox-
active selenocysteine moiety. GPx functions by catalyzing the
reduction of hydrogen peroxide or lipid peroxides with the
tripeptide thiol glutathione. This mitigates the contribution of
peroxides and related reactive oxygen species (ROS) to the
deleterious effects of oxidative stress.3 The latter has, in turn,
been implicated in diverse disorders and disease states,
including inflammation, mutagenesis and cancer, neurodegen-
eration and dementia, cardiovascular disease, and possibly the
aging process.5 Oxidative stress plays an especially detrimental
role during ischemic reperfusion of heart attack and stroke
patients, where ROS produced by neutrophils result in
significant cardiovascular and neurological damage.6 A catalytic
cycle for GPx was first proposed by Ganther and Kraus,7 where
a selenocysteine selenol group serves to reduce the peroxide.
The resulting selenenic acid is then recycled back to the selenol
through sequential reaction with two molecules of glutathione
via the corresponding selenenyl sulfide. Since the protective
effect of GPx can be overwhelmed by conditions of
exceptionally high oxidative stress, such as during ischemic
reperfusion, considerable effort has been expended on the
discovery of small molecule mimetics of the selenoenzyme.5a,8
Two compounds, ebselen9 and ALT 2074,6g,10 reached phase
III and II clinical trials, respectively, for the treatment of various
disorders related to oxidative stress.
observed that the formation of selenenyl sulfides such as 4 (R =
H) dominates at high thiol:peroxide ratios and results in a
competing deactivation pathway, where the corresponding
selenenyl sulfide is relatively inert to further oxidation.11b,c,e
Computational studies on a simpler aliphatic analogue of 1 by
Bayse and Ortwine13 indicated that a selenurane intermediate
analogous to 5 is formed during the initial thiolysis step in
Scheme 1, resulting in the formation of 2. Moreover, they
confirmed that the selenenate ester corresponding to 6 is a
viable intermediate during the reconversion of the selenenic
acid analogous to 3 back to its initial cyclic seleninate ester.
During our earlier investigations, we also observed that
electron-donating groups para to the selenium atom enhanced
the catalytic activity of seleninates 1, whereas electron-
We,11 and Singh et al.,12 have previously studied cyclic
seleninate esters such as 1 as potential GPx mimetics. The
catalytic cycle we proposed for this class of compounds,
employing benzyl thiol as a surrogate for glutathione and
hydrogen peroxide as the oxidant, is shown in Scheme 1 and
proceeds via the thiolseleninate 2 and selenenic acid 3. We also
Received: July 24, 2014
© XXXX American Chemical Society
A
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Note
withdrawing groups suppressed it. A Hammett plot of
seleninate esters 1 provided the reaction constant σ = −0.45,
consistent with a rate-determining step where the transition
state is associated with an increase in positive charge that can be
stabilized mesomerically by electron-donating substituents, as
in the step where Se(II) in 3 (or 6) is oxidized to Se(IV) in
1.11d
Scheme 2
In view of the salutary effect of the p-methoxy substituent of
1b, we embarked on a more extensive study of the effects of
methoxy substituents, including their incorporation at the ortho
and meta positions relative to the selenium center, as well as the
possibility of cumulative effects in di- and trimethoxy-
substituted analogues. Toward this objective, we prepared the
novel cyclic seleninate esters 7−11 (Chart 1) and measured
their catalytic activity by means of an in vitro assay reported
previously.11 The known compounds 1a11c,12a and 1b11d were
included for comparison.
Chart 1
Methoxy groups ortho and para to the selenium atom might
be expected to enhance catalytic activity through mesomeric
electron donation, which generally outweighs their electron-
withdrawing inductive effects, while o-methoxy substituents
could also affect rates through steric or coordination effects. On
the other hand, meta-substituted methoxy groups cannot
interact directly with the selenium atom through resonance,
but can retain their electron-withdrawing inductive effects,
thereby possibly reducing catalytic activity.14 Compounds 7−
11 were made to test the relative contributions of these effects.
In related work, Mugesh and co-workers studied ebselen,9n as
well as diaryl diselenides15 containing methoxy groups present
at either the ortho or para position relative to the selenium
atom. In the diselenides, p-methoxy groups had little effect on
activity when benzenethiol was used as the stoichiometric
reductant, whereas o-methoxy substituents improved catalytic
activity. The latter effect was attributed to steric suppression of
unproductive thiol exchange reactions at selenium that compete
with thiol attack at the sulfur atom in the corresponding
selenenyl sulfides, which were postulated as intermediates.
Wirth16 also reported the GPx activity of a series of diaryl
diselenides, where a p-methoxy substituent improved GPx-like
activity, whereas o-hydroxymethyl or o-methoxymethyl sub-
stituents suppressed it. Coordination effects can also play a
promotive role when O- or N-containing ortho substituents are
present in various types of organoselenium compounds.9n,12,17
The synthesis of m- and o-monomethoxy seleninate esters
7−8 via the corresponding diselenides 14 and 15 is shown in
Scheme 2. The introduction of selenium was accomplished by
ortho-metalation of p- or m-anisaldehyde via the method of
Comins and Brown,18 followed by reaction with elemental
selenium and exposure to air to afford diselenides 12 and 13,
respectively. It proved more expedient to reduce the crude
products directly with lithium aluminum hydride, again
followed by aerial oxidation, to afford the desired hydrox-
ymethyl diselenides 14 and 15. Diselenides 18 and 19 were
prepared more efficiently by transmetalation of the correspond-
ing 2-bromobenzyl alcohols 16 and 17, respectively, while
direct transmetalation and selenization of bromide 24 required
prior protection as the methoxymethyl (MOM) ether 25.
Direct oxidation of diselenides 14, 15, 18, and 19 to the
desired cyclic seleninate esters 7−10 with hydrogen peroxide
afforded relatively low yields of impure products. However, the
conversion of the diselenides to the easily purified allyl
selenides 20−23, followed by one-pot oxidation with excess
hydrogen peroxide, [2,3]sigmatropic rearrangement, and
further oxidation,11 afforded the desired products 7−10,
respectively. Diselenide 26 was obtained and treated similarly,
except that deprotection of the MOM group was effected prior
to oxidation to the cyclic seleninate ester 11.
It is worth noting that the cyclic seleninate esters all showed
nonequivalent methylene proton signals because of the
presence of the chiral selenium atom. In contrast, the related
spirodioxyselenuranes 29,11c,d,19 which are also chiral, displayed
the expected AB quartets at low temperature, which coalesced
to singlets at ca. room temperature and, unexpectedly, split into
new AB quartets upon further heating, as a result of
temperature-dependent chemical shifts of the exo and endo
protons.20,21
B
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ca. 50% completion,23 followed by a significant decrease in its
concentration. This behavior was attributed to the accumu-
lation of the corresponding selenenyl sulfide 30, which was
identified while monitoring the reaction by HPLC.24 An
authentic sample of 30 was prepared by thiolysis of the
seleninate 10 in the absence of hydrogen peroxide (Scheme 3)
Scheme 3
The catalytic activities of compounds 1a, 1b, and 7−11 were
then measured in our previously described assay,11,22 in which
benzyl thiol was oxidized with excess hydrogen peroxide in the
presence of 10 mol % of the catalyst. The formation of dibenzyl
disulfide was monitored by HPLC, and the resulting t1/2 values
are shown in Table 1. Kinetic plots of disulfide formation vs
Table 1. Catalytic Activity of Methoxy-Substituted Cyclic
Seleninate Esters
in order to confirm this assignment. Selenenyl sulfide 30 was
then independently subjected to the assay of its catalytic activity
under the usual conditions, providing a t1/2 value of 69 h, thus
confirming that it is a poorer catalyst than 10 itself.25 The slow
rates of disulfide formation with the o-substituted catalysts 8
and 10 may, therefore, be due to steric suppression of the
normally rate-limiting oxidation of species corresponding to 3
and 6 in Scheme 1. This results in increased formation of the
corresponding less reactive selenenyl sulfides, which then
slowly re-enter the catalytic cycle by disproportionation to the
corresponding diselenides and disulfides, with reoxidation of
the former back to the cyclic seleninates, or by oxidation to the
corresponding thiolseleninates (analogous to 2 in Scheme 1)
and cyclization to regenerate 8 or 10.12c
a
entry
compound
MeO substituent(s)
t1/2 (h)
1
2
3
4
5
6
7
1a
1b
7
none
p
53
38
50
70
49
55
45
m
8
o
9
m,p
o,p
o,m,p
10
11
a
Indicated position is relative to the Se atom; m refers to that meta
position that is also para to the CH2O substituent.
To our knowledge, the late stages (beyond 50% completion)
of the catalytic cycle of cyclic seleninate esters have not yet
been explored. When the assay of 10 was conducted at a higher
temperature (24 °C instead of 18 °C) and monitored beyond
50% completion, the concentration of disulfide decreased
dramatically, as shown in the Supporting Information. This
indicated that, in addition to partial deactivation of the catalyst
through selenenyl sulfide formation, further oxidation of the
disulfide was also taking place. Confirmation of this hypothesis
was provided by the identification of substantial new HPLC
peaks attributed to the thiolsulfinate 31 and benzaldehyde
(Scheme 4). Trace amounts of benzyl sulfonic acid (32) and
methyl benzylsulfinate (35) were also detected. The identi-
fication of these compounds was verified by analysis of the late-
stage reaction by HPLC−HRMS and comparison with the
retention times and mass spectra of authentic samples of the
four new products (see the Supporting Information).
time for catalysts 7−11 in the table are provided in the
Supporting Information. Similar data for 1a and 1b were
reported previously.11d A control reaction with no catalyst
produced a t1/2 of >170 h under the same conditions.
It can be seen that the introduction of a p-methoxy
substituent into the unsubstituted seleninate ester 1a improved
the catalytic activity significantly in 1b (entries 1 and 2), which
can be attributed to the electron-donating mesomeric effect of
the p-methoxy group that stabilizes the developing positive
charge on the selenium atom during its oxidation from Se(II)
to Se(IV) in the rate-determining step. On the other hand, the
m-methoxy substituent of 7 in entry 3, where such a mesomeric
effect is precluded, had almost no effect upon catalytic activity.
Despite the possible resonance interaction between the o-
methoxy group and the selenium atom in 8 (entry 4), this
derivative displayed considerably attenuated activity, suggesting
that the mesomeric effect is overwhelmed by steric inhibition of
the process. This behavior is in contrast to that observed by
Mugesh et al.15 in the case of substituted diaryl diselenides,
where o-methoxy substituents enhanced reactivity. In order to
determine whether the effect of additional methoxy substituents
would be additive to the promotive effect of the p-methoxy
substituent in 1b, we also tested the disubstituted seleninates 9
and 10 (entries 5 and 6), as well as the trisubstituted derivate
11 (entry 7). The m,p-disubstituted and o,m,p-trisubstituted
compounds (entries 5 and 7) proved slightly superior to the
unsubstituted derivative 1a (entry 1), whereas the o,p-
dimethoxy product (entry 6) had essentially the same catalytic
activity as 1a. Surprisingly, however, seleninates 9−11 all
showed decreased catalytic activity compared to the p-
monomethoxy compound 1b (entry 2). Furthermore, in the
case of 10, the formation of the disulfide essentially stopped at
Scheme 4
C
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Note
ment. The mass spectra were obtained by ESI with a quadrupole TOF
analyzer.
Since cyclic seleninate esters are known to catalyze the
oxidation of sulfides to sulfoxides with hydrogen peroxide,26 it
is reasonable to expect that a similar process produces 31 from
dibenzyl disulfide in the later stages of the reaction, where the
disulfide is abundant and competes with the more reactive, but
now depleted, thiol. Furthermore, thiolsulfinate 31 is known to
generate, inter alia, the corresponding sulfinic acid and sulfine
33 upon further oxidation.27,28 The presence of benzyl sulfinic
acid could not be confirmed in the present reaction mixture,
but its further oxidation to the observed sulfonic acid 32 is
plausible. Sulfines, in turn, are known to hydrolyze,27,29,30 or
rearrange to oxathiiranes, followed by extrusion of sulfur,29,31 to
produce carbonyl compounds, thus providing a rationale for the
formation of benzaldehyde. Methanolysis of 31 or 33 affords
the sulfinate ester 35 (Scheme 4).
In conclusion, the most effective substitution pattern in the
methoxy-substituted series of catalysts for the oxidation of
benzyl thiol with hydrogen peroxide is the single p-methoxy
substituent in 1b and neither the introduction of lone methoxy
groups at the ortho or meta positions (relative to selenium) nor
their introduction in addition to an existing p-methoxy group
conferred further significant improvements in catalytic activity.
The presence of the o-methoxy group in compounds 8 and 10
proved especially deleterious, despite the expected enhance-
ment of catalytic activity through electron donation to selenium
through resonance. We attribute this behavior to steric
suppression of the rate-limiting oxidation of Se(II) inter-
mediates to Se(IV), along with enhanced formation of the less
catalytically active selenenyl sulfide 30. It was also found that, in
the case of the o,p-dimethoxy compound 10, significant further
oxidation of the product dibenzyl disulfide occurred in later
stages of the catalytic process, as evidenced by the formation of
the corresponding thiolsulfinate 31 and benzaldehyde, along
with traces of benzyl sulfonic acid and the methyl sulfinate 35.
(2-{[2-(Hydroxymethyl)-5-methoxyphenyl]diselanyl}-4-
methoxyphenyl)methanol (14). A solution of N,N,N′-trimethyl-
ethylenediamine (0.840 mL, 660 mg, 6.46 mmol) in 20 mL of dry
THF was cooled to −20 °C under nitrogen, and n-butyllithium (2.6
mL, 2.4 M, 6.2 mmol) was added. After 15 min, 4-methoxy-
benzaldehyde (0.73 mL, 0.82 g, 6.0 mmol) was added, and the mixture
was left at −20 °C for an additional 15 min. A second portion of n-
butyllithium (2.6 mL, 2.4 M 6.2 mmol) was then added, and the
mixture was warmed to 0 °C and left for 1.5 h. Elemental selenium
(553 mg, 7.00 mmol) was quickly introduced, and the nitrogen
atmosphere was restored. The mixture was warmed to room
temperature, stirred for an additional 3 h, and then poured into a
mixture of 30 mL of 1 M HCl and 30 mL of ethyl acetate. Air was
rapidly bubbled through the mixture for 30 min, and the mixture was
extracted with ethyl acetate, washed with brine, dried, and
concentrated under reduced pressure to afford crude diselenide 12
(1.27 g) as a red solid.
The above product was suspended in 10 mL of dry THF and added
to a suspension of lithium aluminum hydride (750 mg, 19.8 mmol) in
40 mL of THF at 0 °C. The mixture was warmed to room temperature
and stirred for an additional 4 h. It was then cooled to 0 °C and
carefully quenched with water. Ethyl acetate was added, and the
resulting slurry was filtered to remove the solid precipitate. The
aqueous layer from the filtrate was extracted with ethyl acetate, and the
aqueous layer was stirred in the presence of air for 12 h. During this
time, diselenide 14 crystallized as a yellow solid (595 mg, 46%
overall); mp 101−102 °C (from ethyl acetate−hexanes); IR (ATR)
1
3301, 1602, 1468, 1245, 1009 cm−1; H NMR (400 MHz; CDCl3) δ
7.27 (d, J = 8.8 Hz, 2 H), 7.26 (d, J = 2.4 Hz, 2 H), 6.80 (dd, J = 8.4,
2.8 Hz, 2 H), 4.70 (s, 4 H), 3.73 (s, 6 H), 1.88 (br s, 2 H); 13C NMR
(101 MHz; CDCl3) δ 159.7, 134.2, 132.2, 129.9, 119.8, 114.7, 65.1,
55.5; 77Se NMR (76 MHz; CDCl3) δ 437.1; mass spectrum (EI-TOF)
m/z (relative intensity) 434 (38, M+), 215 (68), 201 (70), 108 (100);
HRMS (EI-TOF) m/z (M+) calcd for C16H18O480Se2: 433.9536;
found: 433.9548. Anal. Calcd for C16H18O4Se2: C, 44.46; H, 4.20;
found: C, 44.50; H, 4.15.
(2-{[2-(Hydroxymethyl)-6-methoxyphenyl]diselanyl}-3-
methoxyphenyl)methanol (15). The same procedure was
employed as for the preparation of 14. Yield: 54% (overall). Yellow
solid, mp 142−144 °C (from hexanes−ethyl acetate); IR (ATR) 3281,
1571, 1462, 1267, 1033 cm−1; 1H NMR (400 MHz; CDCl3) δ 7.31 (t,
J = 8.0 Hz, 2 H), 7.05 (dd, J = 7.6, 1.2 Hz, 2 H), 6.81 (dd, J = 8.4, 0.80
Hz, 2 H), 4.62 (d, J = 6.4 Hz, 4 H), 3.69 (s, 6 H), 2.24 (t, J = 6.6 Hz, 2
H); 13C NMR (101 MHz; CDCl3) δ 160.3, 146.3, 131.3, 121.1, 119.6,
110.6, 65.8, 56.3; 77Se NMR (76 MHz; CDCl3) δ 355.5; mass
spectrum (EI-TOF) m/z (relative intensity) 434 (48, M+), 216 (46),
200 (100), 108 (98); HRMS (EI-TOF) m/z (M+) calcd for
C16H18O480Se2: 433.9536; found: 433.9532. Anal. Calcd for
C16H18O4Se2: C, 44.46; H, 4.20; found: C, 44.38; H, 4.32.
(2-{[2-(Hydroxymethyl)-4,5-dimethoxyphenyl]diselanyl}-4,5-
dimethoxyphenyl)methanol (18). 2-Bromo-4,5-dimethoxybenzyl
alcohol (3.13 g, 12.7 mmol) was dissolved in 130 mL of dry THF and
cooled to −78 °C under nitrogen. n-Butyllithium (14.3 mL, 2.00 M,
28.6 mmol) was added, and the mixture was warmed to 0 °C over 45
min. Elemental selenium (2.25 g, 28.5 mmol) was added, and the
nitrogen atmosphere was restored. The mixture was stirred for 3 h at
room temperature and was then quenched with 80 mL of saturated
ammonium chloride solution. Air was rapidly bubbled through the
mixture for 30 min, and the mixture was washed with brine, dried, and
concentrated under reduced pressure. The resulting oil was purified by
flash chromatography (gradient of hexanes−ethyl acetate, 2:1 to 100%
ethyl acetate) to afford 1.67 g (54%) of diselenide 18 as a yellow solid,
mp 148−150 °C (from ethyl acetate); IR (ATR) 3349, 1584, 1494,
1259, 1213, 1150, 1032 cm−1; 1H NMR (400 MHz; CDCl3) δ 7.01 (s,
2 H), 6.98 (s, 2 H), 4.60 (s, 4 H), 3.89 (s, 6 H), 3.76 (s, 6 H), 2.08 (br
s, 2 H); 13C NMR (101 MHz; CDCl3) δ 150.6, 148.4, 137.2, 120.7,
120.0, 111.6, 65.3, 56.2, 56.1; 77Se NMR (76 MHz; CDCl3) δ 467.6;
mass spectrum (EI-TOF) m/z (relative intensity) 494 (9, M+), 245
EXPERIMENTAL SECTION
■
Hydrogen peroxide was titrated prior to use,32 and benzyl thiol was
redistilled. Starting materials 16, 17, and 24 are commercially available
but were also prepared by bromination of the corresponding benzyl
alcohols by standard methods. Authentic samples of thiolsulfinate
31,33,34 sulfonic acid 32,35 and sulfinate ester 3536 were prepared by
literature methods.
1
Spectroscopic Experiments. H NMR spectra were recorded at
400 MHz, while 13C and 77Se NMR spectra were obtained at 101 and
76 MHz, respectively. Chemical shifts of 77Se NMR spectra were
obtained with diphenyl diselenide in CDCl3 (463.0 ppm)37 as the
standard, relative to dimethyl selenide (0.0 ppm). High-resolution
mass spectra were obtained using a time-of-flight (TOF) analyzer with
electron impact (EI) ionization or a quadrupole TOF analyzer with
electrospray ionization (ESI).
HPLC Assay for Catalytic Activity. Catalytic activity was
measured by adding the catalyst (0.031 mmol, 10 mol % relative to
thiol) to a mixture of hydrogen peroxide (0.035 M) and redistilled
benzyl thiol (0.031 M) in 10.0 mL of dichloromethane−methanol
(95:5) while maintaining the temperature at 18 °C. The reactions were
monitored by HPLC analysis, using a UV detector at 254 nm and a
reversed phase column (Novapak C18; 3.9 × 150 mm). Acetonitrile−
water was employed as the solvent (gradient: 60:40 to 80:20 over 15
min with a flow rate of 0.9 mL/min). Naphthalene (0.0080 M) was
employed as the internal standard. The values of t1/2 were determined
by plotting the yield (%) of the product disulfide vs time and represent
the time required for conversion of 50% of the thiol into its disulfide.
The t1/2 values are the average of at least two runs.
HPLC−MS Analysis. The same HPLC column and solvent system
as above were employed, except that the gradient was altered as
required to better separate individual peaks for exact mass measure-
D
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Note
(20), 230 (24), 138 (100); HRMS (EI-TOF) m/z (M+) calcd for
C18H22O680Se2Na (ESI, M + Na+): 516.9639; found: 516.9642.
(2-{[2-(Hydroxymethyl)-4,6-dimethoxyphenyl]diselanyl}-3,5-
dimethoxyphenyl)methanol (19). 2-Bromo-3,5-dimethoxybenzyl
alcohol (1.00 g, 4.05 mmol) was dissolved in 50 mL of dry THF and
cooled to −78 °C under a nitrogen atmosphere. n-Butyllithium (3.7
mL, 2.4 M, 8.9 mmol) was added, and the mixture was warmed to
room temperature over 1 h. Elemental selenium (355 mg, 4.50 mmol)
was added, and the nitrogen atmosphere was restored. The mixture
was stirred at room temperature for an additional 3 h and was then
quenched with 30 mL of saturated ammonium chloride solution. Air
was rapidly bubbled through the mixture for 30 min, and the mixture
was washed with brine, dried, and concentrated under reduced
pressure. Flash chromatography (100% ethyl acetate) provided an
inseparable mixture of diselenide 19 and the corresponding selenide in
the ratio of ca. 3:1. This mixture was used in subsequent steps without
further purification, as it was easier to separate the selenide at a later
stage.
Hz, 2 H), 2.38 (t, J = 9.2 Hz, 1 H); 13C NMR (101 MHz; CDCl3) δ
161.5, 161.1, 147.2, 134.9, 116.3, 107.4, 105.0, 98.0, 66.1, 56.1, 55.4,
30.1; 77Se NMR (76 MHz; CDCl3) δ 162.6; mass spectrum (EI-TOF)
m/z (relative intensity) 288 (52, M+), 247 (22), 166 (100), 138 (78);
HRMS (EI-TOF) m/z (M+) calcd for C12H16O380Se: 288.0265; found:
288.0262.
During chromatography of allyl selenide 23, 50 mg of the
corresponding symmetrical aryl selenide analogue of 19 was also
isolated as a byproduct from the preparation of 19. Colorless solid, mp
159−161 °C (from ethyl acetate); IR (ATR) 3252, 1586, 1462, 1310,
1157 cm−1; 1H NMR (400 MHz; CDCl3) δ 6.62 (d, J = 2.4 Hz, 2 H),
6.33 (d, J = 2.4 Hz, 2 H), 4.84 (d, J = 6.4 Hz, 4 H), 3.80 (s, 6 H), 3.63
(s, 6 H), 3.31 (t, J = 6.6 Hz, 2 H); 13C NMR (101 MHz; CDCl3) δ
161.2, 160.5, 146.2, 110.0, 106.4, 98.8, 66.4, 56.2, 55.5; 77Se NMR (76
MHz; CDCl3) δ 122.8; mass spectrum (EI-TOF) m/z (relative
intensity) 414 (46, M+), 246 (44), 230 (30), 165 (100), 139 (64);
HRMS (EI-TOF) m/z (M+) calcd for C18H22O680Se: 414.0582; found:
414.0598.
Typical Procedure for the Preparation of Allyl Aryl
Selenides: [4-Methoxy-2-(prop-2-en-1-ylselanyl)phenyl]-
methanol (20). Diselenide 14 (200 mg, 0.463 mmol) was dissolved
in 18 mL of THF−ethanol (5:1) and cooled to 0 °C. Sodium
borohydride (122 mg, 3.22 mmol) was added, followed after 5 min by
allyl iodide (0.145 mL, 266 mg, 1.58 mmol). The mixture was stirred
at room temperature for an additional 3 h and was then quenched with
15 mL of water. The mixture was extracted with ethyl acetate, washed
with brine, dried, and concentrated under reduced pressure. The
resulting oil was purified by flash chromatography (hexanes−ethyl
acetate, 2:1) to afford 215 mg (90%) of the product 20 as a colorless
Typical Procedure for the Preparation of Cyclic Seleninate
Esters: 6-Methoxy-3H-benzo[c]-1,2-oxaselenole-1-oxide (7).
Allyl selenide 20 (186 mg, 0.723 mmol) and 29% H2O2 (0.260 mL,
2.2 mmol) were stirred in 10 mL of dichloromethane for 16 h. The
solution was concentrated, and the resulting mixture was purified by
flash chromatography (ethyl acetate-methanol, 9:1) to afford 137 mg
(81%) of the cyclic seleninate ester 7 as a colorless solid, mp 148−149
°C (from ethyl acetate-methanol); IR (ATR) 1598, 1472, 1257, 1230,
1023 cm−1; 1H NMR (400 MHz; CDCl3) δ 7.35 (d, J = 8.8 Hz, 1 H),
7.25 (d, J = 2.4 Hz, 1 H), 7.10 (dd, J = 8.4, 2.4 Hz, 1 H), 5.90 (d, J =
12.8 Hz, 1 H), 5.56 (d, J = 13.2 Hz, 1 H), 3.81 (s, 3 H); 13C NMR
(101 MHz; CDCl3) δ 160.5, 149.3, 135.2, 123.4, 119.9, 108.9, 78.4,
55.9; 77Se NMR (76 MHz; CDCl3) δ 1348.5; mass spectrum (EI-
TOF) m/z (relative intensity) 232 (38, M+), 215 (24), 136 (100), 108
(46); HRMS (EI-TOF) m/z (M+) calcd for C8H8O380Se: 231.9639;
found: 231.9642. Anal. Calcd for C8H8O3Se: C, 41.58; H, 3.49; found:
C, 41.40; H, 3.35.
1
oil; IR (neat) 3438, 1600, 1476, 1233, 1038 cm−1; H NMR (400
MHz; CDCl3) δ 7.26 (d, J = 8.4 Hz, 1 H), 7.06 (d, J = 2.8 Hz, 1 H),
6.76 (dd, J = 8.4, 2.8 Hz, 1 H), 5.97−5.87 (m, 1 H), 4.99 (ddt, J =
16.9, 2.6, 1.3 Hz, 1 H), 4.96−4.93 (m, 1 H), 4.65 (d, J = 6.0 Hz, 2 H),
3.77 (s, 3 H), 3.49 (br d, J = 7.6 Hz, 2 H), 2.54 (t, J = 6.2 Hz, 1 H);
13C NMR (101 MHz; CDCl3) δ 159.1, 135.0, 134.2, 131.1, 129.6,
119.7, 117.3, 112.9, 64.8, 55.4, 30.8; 77Se NMR (76 MHz; CDCl3) δ
269.0; mass spectrum (EI-TOF) m/z (relative intensity) 258 (64, M+),
217 (96), 159 (30), 135 (36), 108 (100); HRMS (EI-TOF) m/z (M+)
calcd for C11H14O280Se: 258.0159; found: 258.0160. Anal. Calcd for
C11H14O2Se: C, 51.37; H, 5.49; found: C, 51.33; H, 5.63.
7-Methoxy-3H-benzo[c]-1,2-oxaselenole-1-oxide (8). Pre-
pared from allyl selenide 21 by the same procedure as for 7. Yield:
85%. Colorless solid; mp 156−157 °C (from ethyl acetate−methanol);
1
IR (ATR) 1567, 1468, 1275, 1068, 964 cm−1; H NMR (400 MHz;
CDCl3) δ 7.50 (t, J = 8.0 Hz, 1 H), 6.99 (dd, J = 7.6 Hz, 0.8 Hz, 1 H),
6.89 (d, J = 8.0 Hz, 1 H), 5.95 (d, J = 14.0 Hz, 1 H), 5.58 (d, J = 13.6
Hz, 1 H), 3.91 (s, 3 H); 13C NMR (101 MHz; CDCl3) δ 157.4, 146.3,
136.3, 134.7, 114.5, 110.4, 79.2, 56.2; 77Se NMR (76 MHz; CDCl3) δ
1341.7; HRMS (ESI-TOF) m/z (M + H)+ calcd for C8H9O380Se:
232.9717; found: 232.9712. Anal. Calcd for C8H8O3Se: C, 41.58; H,
3.49; found: C, 41.66; H, 3.38.
[3-Methoxy-2-(prop-2-en-1-ylselanyl)phenyl]methanol (21).
Prepared from diselenide 15 by the same procedure as for 20. Yield:
86%. Colorless oil; IR (neat) 3462, 1633, 1567, 1471, 1248, 1176
1
cm−1; H NMR (400 MHz; CDCl3) δ 7.30 (t, J = 8.0 Hz, 1 H), 7.03
(dd, J = 7.6, 0.8 Hz, 1 H), 6.84 (dd, J = 8.2, 1.0 Hz, 1 H), 5.90−5.79
(m, 1 H), 4.84−4.82 (m, 1 H), 4.79 (br s, 1 H), 4.77 (d, J = 6.8 Hz, 2
H), 3.90 (s, 3 H), 3.48 (d, J = 7.6 Hz, 2 H), 2.50 (t, J = 6.6 Hz, 1 H);
13C NMR (101 MHz; CDCl3) δ 160.1, 146.1, 134.9, 130.0, 121.1,
5,6-Dimethoxy-3H-benzo[c]-1,2-oxaselenole-1-oxide (9).
Prepared from allyl selenide 22 by the same procedure as for 7.
Yield: 87%. Colorless solid; mp 168−169 °C (from ethyl acetate−
117.0, 116.5, 110.4, 66.1, 56.2, 30.0; 77Se NMR (76 MHz; CDCl3) δ
178.4; mass spectrum (EI-TOF) m/z (relative intensity) 258 (100,
M+), 217 (72), 199 (32), 108 (90); HRMS (EI-TOF) m/z (M+) calcd
for C11H14O280Se: 258.0159; found: 258.0157. Anal. Calcd for
C11H14O2Se: C, 51.37; H, 5.49; found: C, 51.39; H, 5.50.
1
methanol); IR (film) 1576, 1497, 1280, 1215, 1030 cm−1; H NMR
(400 MHz; CDCl3) δ 7.23 (s, 1 H), 6.86 (s, 1 H), 5.89 (d, J = 13.2 Hz,
1 H), 5.52 (d, J = 13.6 Hz, 1 H), 3.91 (s, 3 H), 3.86 (s, 3 H); 13C
NMR (101 MHz; CDCl3) δ 152.8, 150.1, 139.0, 137.0, 107.0, 104.2,
78.7, 56.37, 56.35; 77Se NMR (76 MHz; CDCl3) δ 1355.9; mass
spectrum (EI-TOF) m/z (relative intensity) 262 (6, M+), 166 (100),
138 (26); HRMS (ESI-TOF) m/z (M + H)+ calcd for C9H11O480Se:
262.9818; found: 262.9819. Anal. Calcd for C9H10O4Se: C, 41.40; H,
3.86; found: C, 41.22; H, 4.10.
[4,5-Dimethoxy-2-(prop-2-en-1-ylselanyl)phenyl]methanol
(22). Prepared from diselenide 18 by the same procedure as for 20.
Yield: 79%. Brown oil; IR (neat) 3490, 1602, 1498, 1267, 1148, 1036
1
cm−1; H NMR (400 MHz; CDCl3) δ 7.04 (s, 1 H), 6.94 (s, 1 H),
5.92−5.81 (m, 1 H), 4.87−4.79 (m, 2 H), 4.69 (s, 2 H), 3.83 (s, 3 H),
3.82 (s, 3 H), 3.36 (d, J = 7.2 Hz, 2 H), 2.54 (br s, 1 H); 13C NMR
(101 MHz; CDCl3) δ 149.3, 148.1, 137.0, 134.6, 119.5, 118.9, 116.8,
111.6, 65.3, 56.1, 55.9, 31.9; 77Se NMR (76 MHz; CDCl3) δ 273.1;
mass spectrum (EI-TOF) m/z (relative intensity) 288 (27, M+), 247
(24), 138 (100); HRMS (EI-TOF) m/z (M+) calcd for C12H16O380Se:
288.0265; found: 288.0275.
5,7-Dimethoxy-3H-benzo[c]-1,2-oxaselenole-1-oxide (10).
Prepared from allyl selenide 23 by the same procedure as for 7.
Yield: 89%. Colorless solid; mp 149−151 °C (from ethyl acetate−
1
methanol); IR (ATR) 1590, 1467, 1352, 1224, 1157 cm−1; H NMR
(400 MHz; CDCl3) δ 6.46 (d, J = 2.0 Hz, 1 H), 6.41 (d, J = 1.6 Hz, 1
H), 5.90 (d, J = 13.6 Hz, 1 H), 5.50 (d, J = 14.0 Hz, 1 H), 3.88 (s, 3
H), 3.84 (s, 3 H); 13C NMR (101 MHz; CDCl3) δ 165.6, 158.5, 148.1,
128.6, 98.7, 98.2, 78.9, 56.2, 56.1; 77Se NMR (76 MHz; CDCl3) δ
1355.1; HRMS (ESI-TOF) m/z (M + H)+ calcd for C9H11O480Se:
262.9818; found: 262.9814. Anal. Calcd for C9H10O4Se: C, 41.40; H,
3.86; found: C, 41.57; H, 3.81.
[3,5-Dimethoxy-2-(prop-2-en-1-ylselanyl)phenyl]methanol
(23). Prepared from diselenide 19 by the same procedure as for 20.
Yield: 51% overall from benzyl alcohol 17. Colorless oil; IR (neat)
1
3452, 1590, 1462, 1152, 1067 cm−1; H NMR (400 MHz; CDCl3) δ
6.63 (d, J = 3.6 Hz, 1 H), 6.42 (d, J = 3.2 Hz, 1 H), 5.92−5.78 (m, 1
H), 4.83−4.75 (m, 4 H), 3.88 (s, 3 H), 3.83 (s, 3 H), 3.40 (d, J = 10.4
E
dx.doi.org/10.1021/jo501689h | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
2-Bromo-3,4,5-trimethoxy-1-[(methoxymethoxy)methyl]-
benzene (25). 2-Bromo-3,4,5-trimethoxybenzyl alcohol (800 mg,
2.89 mmol) was dissolved in 10 mL of dichloromethane.
Diisopropylethylamine (0.610 mL, 453 mg, 3.50 mmol) was added,
followed by chloromethyl methyl ether (0.265 mL, 281 mg, 3.47
mmol). After 14 h of stirring at room temperature, the mixture was
poured into 20 mL of water. The aqueous layer was extracted with
ethyl acetate, and the combined organic layers were washed with brine,
dried, and concentrated under reduced pressure. The resulting oil was
purified by flash chromatography (hexanes−ethyl acetate, 1:1) to
afford 845 mg (91%) of the MOM-protected alcohol 25 as a colorless
(from ethyl acetate−methanol); IR (ATR) 1576, 1460, 1340, 1104
cm−1; 1H NMR (400 MHz; CDCl3) δ 6.62 (s, 1 H), 5.91 (d, J = 13.6
Hz, 1 H), 5.53 (d, J = 13.6 Hz, 1 H), 4.08 (s, 3 H), 3.90 (s, 3 H), 3.86
(s, 3 H); 13C NMR (101 MHz; CDCl3) δ 158.6, 150.6, 140.8, 140.4,
133.0, 99.8, 79.3, 61.9, 61.3, 56.6; 77Se NMR (76 MHz; CDCl3) δ
1360.5; mass spectrum (EI-TOF) m/z (relative intensity) 292 (20,
M+), 276 (12), 196 (100); HRMS (EI-TOF) m/z (M+) calcd for
C10H12O580Se: 291.9850; found: 291.9855. Anal. Calcd for
C10H12O5Se: C, 41.25; H, 4.15; found: C, 41.31; H, 4.07.
{2-[(Benzylsulfanyl)selanyl]-3,5-dimethoxyphenyl}methanol
(30). Seleninate ester 10 (131 mg, 0.502 mmol) was dissolved in
dichloromethane (0.03 M) and cooled to 0 °C. Benzyl thiol (0.18 mL,
1.5 mmol) was added, and the solution was stirred for 1 h,
concentrated in vacuo, and immediately chromatographed (hex-
anes−ethyl acetate, 6:1) to give 171 mg (92%) of 30 as a yellow
solid: mp 81−83 °C; IR (film) 3385, 1569, 1449, 1379, 1260, 1110
cm−1; 1H NMR (400 MHz; CDCl3) δ 7.29−7.21 (m, 5 H), 6.69 (d, J
= 2.4 Hz, 1 H), 6.42 (d, J = 2.5 Hz, 1 H), 4.86 (s, 2 H), 4.11 (s, 2 H),
3.87 (s, 3 H), 3.84 (s, 3 H); 13C NMR (101 MHz; CDCl3) δ 162.7,
161.6, 147.6, 138.7, 129.2, 128.7, 127.5, 105.5, 98.2, 66.3, 56.3, 55.7,
42.7; 77Se NMR (76 MHz; CDCl3) δ 341.1; HRMS (ESI-TOF) m/z
(M + H)+ calcd for C16H19O3S80Se: 371.0215; found; 371.0208. Anal.
Calcd for C16H18O3SSe: C, 52.03; H, 4.91; found: C, 52.00; H, 4.73.
{[Benzylsulfanyl)sulfinyl]methyl}benzene (31).33 The product
was obtained by the method of Pratt et al.33a in 55% yield: white solid;
mp 79−81 °C (from ether) (lit.33c,e mp 130 °C; lit.33d mp 86 °C;); IR
(film); 3019, 1448, 1081, 1052 cm−1; 1H NMR (400 MHz; CDCl3) δ
7.36−7.23 (m, 10 H), 4.32 (d, J = 12.9 Hz, 1 H), 4.28 (d, J = 13.5 Hz,
1 H), 4.26 (d, J = 12.9 Hz, 1 H); 4.24 (d, J = 13.5 Hz, 1 H); 13C NMR
(101 MHz; CDCl3) δ 136.8, 130.6, 130.2, 129.3, 129.0, 128.9, 128.0,
62.4, 36.4; HRMS (ESI-TOF) m/z (M + H)+ calcd for C14H15OS2:
263.0559; found: 263.0560. Anal. Calcd for C14H14OS2: C, 64.08; H,
5.38; found: C, 64.10; H, 5.42.
1
oil; IR (neat) 1576, 1481, 1324, 1152 cm−1; H NMR (400 MHz;
CDCl3) δ 6.87 (s, 1 H), 4.75 (s, 2 H), 4.61 (s, 2 H), 3.88 (s, 3 H),
3.864 (s, 3 H), 3.861 (s, 3 H), 3.43 (s, 3 H); 13C NMR (101 MHz;
CDCl3) δ 152.9, 151.0, 142.6, 133.0, 109.1, 108.2, 96.3, 69.1, 61.2,
61.1, 56.3, 55.7; mass spectrum (EI-TOF) m/z (relative intensity) 320
(68, M+), 259 (84), 181 (100); HRMS (EI-TOF) m/z (M+) calcd for
C12H1779BrO5: 320.0259; found: 320.0261. Anal. Calcd for
C12H17BrO5: C, 44.88; H, 5.34; found: C, 44.60; H, 5.15.
1,2,3-Trimethoxy-5-[(methoxymethoxy)methyl]-4-({2,3,4-tri-
methoxy-6-[(methoxymethoxy)methyl]phenyl}diselanyl)-
benzene (26). Aryl bromide 25 (1.30 g, 4.69 mmol) was dissolved in
40 mL of dry THF and cooled to −78 °C under a nitrogen
atmosphere. n-Butyllithium (3.0 mL, 1.9 M, 5.7 mmol) was added, and
the mixture was warmed to 0 °C over 1.5 h. Elemental selenium (450
mg, 5.70 mmol) was quickly introduced, and the nitrogen atmosphere
was restored. The mixture was warmed to room temperature, left for
an additional 3 h, and then quenched with 40 mL of saturated
ammonium chloride solution. Air was rapidly bubbled through the
mixture for 30 min, and the mixture was washed with brine, dried, and
concentrated under reduced pressure. The resulting oil was purified by
flash chromatography (hexanes−ethyl acetate, 1:2) to afford 850 mg
(58%) of the product 26 as a yellow oil, which was used in subsequent
steps immediately.
1,2,3-Trimethoxy-5-[(methoxymethoxy)methyl]-4-(prop-2-
en-1-ylselanyl)benzene (27). Prepared from diselenide 26 by the
same procedure as for 20. Yield: 72%. Colorless oil; IR (neat) 1586,
1476, 1324, 1095 cm−1; 1H NMR (400 MHz; CDCl3) δ 6.87 (s, 1 H),
5.92−5.81 (m, 1 H), 4.84 (d, J = 16.8 Hz, 1 H), 4.80 (d, J = 10.4 Hz, 1
H), 4.742 (s, 2 H), 4.736 (s, 2 H), 3.93 (s, 3 H), 3.88 (s, 3 H), 3.87 (s,
3 H), 3.46−3.44 (m, 2 H), 3.44 (s, 3 H); 13C NMR (101 MHz;
CDCl3) δ 155.3, 154.1, 142.0, 137.8, 135.0, 116.3, 115.3, 108.1, 96.3,
70.4, 61.1, 61.0, 56.2, 55.7, 31.0; 77Se NMR (76 MHz; CDCl3) δ
197.7; mass spectrum (EI-TOF) m/z (relative intensity) 362 (80, M+),
289 (100), 259 (25); HRMS (EI-TOF) m/z (M+) calcd for
C15H22O580Se: 362.0632; found: 362.0623.
[3,4,5-Trimethoxy-2-(prop-2-en-1-ylselanyl)phenyl]-
methanol (28). Allyl selenide 27 (147 mg, 0.408 mmol) was
dissolved in 5 mL of methanol. Concentrated HCl (6 drops) was
added, and the mixture was heated at 60 °C. After 5 h, the methanol
solution was poured into 5 mL of saturated sodium bicarbonate
solution. The mixture was extracted with ethyl acetate, washed with
brine, dried, and concentrated under reduced pressure. The resulting
oil was purified by flash chromatography (hexanes−ethyl acetate, 1:2)
to afford 97 mg (75%) of the free alcohol 28 as a slightly yellow oil; IR
(neat) 3424, 2929, 1590, 1481, 1319, 1100 cm−1; 1H NMR (400
MHz; CDCl3) δ 6.80 (s, 1 H), 5.91−5.80 (m, 1 H), 4.85−4.82 (m, 1
H), 4.80 (m, 1 H), 4.72 (br s, 2 H), 3.92 (s, 3 H), 3.87 (s, 3 H), 3.85
(s, 3 H), 3.45 (br d, J = 7.6 Hz, 2 H), 2.48 (br s, 1 H); 13C NMR (101
MHz; CDCl3) δ 155.3, 154.2, 141.8, 140.7, 134.9, 116.7, 113.9, 107.9,
66.1, 61.2, 61.0, 56.1, 30.9; 77Se NMR (76 MHz; CDCl3) δ 194.4;
mass spectrum (EI-TOF) m/z (relative intensity) 318 (54, M+), 277
(44), 196 (30), 168 (100), 153 (34); HRMS (EI-TOF) m/z (M+)
calcd for C13H18O480Se: 318.0370; found: 318.0364.
ASSOCIATED CONTENT
* Supporting Information
■
S
1H, 13C, and 77Se NMR spectra for new compounds and for
thiolsulfinate 31; kinetic plots for assays of compounds 7−11
and 30; and HPLC and HRMS data for the assay of compound
10. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: tgback@ucalgary.ca (T.G.B.).
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Natural Sciences and Engineering Research
Council of Canada (NSERC) for financial support. D.J.P. and
N.M.R.M. thank NSERC and Alberta Innovates-Technology
Futures (AI-TF) for postgraduate scholarships. M.H. acknowl-
edges receipt of an NSERC Undergraduate Student Research
Assistantship.
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anomalous kinetics at around the 50% completion stage of the
reaction. The indicated value of 55 h in Table 1 was the average of
seven runs with individual values ranging between 43 and 65 h.
(24) HPLC measurements indicated that conversion of the catalyst
10 to the selenenyl sulfide 30 was 39% complete after 0.5 h and 89%
complete after 27 h.
(25) Most of the cyclic seleninate esters that we have investigated to
date have produced linear kinetic plots to at least the 50% completion
point, whereas 1a showed linear behavior to at least 70% completion.
However, in some cases, we have noticed that the increase in disulfide
concentration slowed considerably, well before completion (e.g., see
ref 11e). This can be attributed to the accumulation of the
corresponding selenenyl sulfides, which are generally poorer catalysts
than the seleninate esters (refs 11b and 11c).
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(28) A reviewer has suggested the possibility that the benzyl thiol is
first oxidized to the sulfenic acid (BnSOH) and then to the sulfonic
acid 32 via the corresponding sulfinic acid and that the sulfenic acid
could also be the precursor of the thiolsulfinate 31. Although we
cannot rule out the formation of 32 in this way unequivocally, it is
likely that the sulfenic acid, if produced in this manner, would react
rapidly with additional thiol to produce dibenzyl disulfide, which could
then be oxidized to 31 in a subsequent step as shown in Scheme 4.
(29) For a review of sulfines, see: Zwanenburg, B. Recl. Trav. Chim.
Pays-Bas 1982, 101, 1−27.
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The Journal of Organic Chemistry
Note
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(32) Hydrogen peroxide was titrated by the procedure described in:
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1989; pp 372−373.
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(34) Several literature reports indicate that the 1H NMR spectrum of
31 contains singlets for one (ref 33a) or both (ref 33c) of the
methylene groups. Our spectrum shows diastereotopic hydrogens on
both methylene groups and matches most closely the spectrum
reported by Freeman et al. (ref 33b). The NMR spectrum is
apparently highly sensitive to solvent effects (ref 33c). In view of these
discrepancies, we are providing full characterization data for this
1
compound in the Experimental Section and copies of our H and 13C
NMR spectra in the Supporting Information.
(35) Bravo, A.; Dordi, B.; Fontana, F.; Minisci, F. J. Org. Chem. 2001,
66, 3232−3234.
(36) Brownbridge, P.; Jowett, I. C. Synthesis 1988, 252−254.
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H
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