Seleno-Michael Reaction of Stable Functionalised Alkyl Selenols: A Versatile Tool for the Synthesis of Acyclic and Cyclic Unsymmetrical Alkyl and Vinyl Selenides

Article abstract of DOI:10.1002/adsc.201900168

Seleno-Michael additions of stable functionalised primary alkyl selenols to activated alkenes and alkynes are described. In the presence of Al₂O₃, β-hydroxy-, β-amino-, and β-mercapto selenols react smoothly with electron-poor alkenes and alkynes to afford the corresponding unsymmetrical functionalised dialkyl- and alkyl?vinyl-selenides in good yield. The very mild conditions allow a broad range of selenols and Michael acceptors to be converted into the corresponding synthetically valuable seleno-Michael adducts, demonstrating high selectivity and excellent functional group tolerance. Hydroxy- and mercapto-substituted vinyl selenides were efficiently employed for the synthesis of functionalised 1,3-oxaselenolanes, 1,3-thiaselenolanes, and 1,4-thiaselenanes through intramolecular oxa- and thia-Michael additions. Furthermore, a NaH-promoted lactonization enables the synthesis of variously substituted 2-oxo-1,4-oxaselenanes from hydroxy?vinyl-selenides. Evaluation of thiol peroxidase-like properties of novel functionalised organoselenides demonstrated that they possess a remarkable catalytic antioxidant activity. (Figure presented.).

Full text of DOI:10.1002/adsc.201900168

Title: Seleno-Michael Reaction of Stable Functionalised Alkyl
Selenols: A Versatile Tool for the Synthesis of Acyclic and Cyclic
Unsymmetrical Alkyl and Vinyl Selenides
Authors: Damiano Tanini, Simone Scarpelli, Elena Ermini, and
Antonella Capperucci
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10.1002/adsc.201900168
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Seleno-Michael Reaction of Stable Functionalised Alkyl
Selenols: A Versatile Tool for the Synthesis of Acyclic and
Cyclic Unsymmetrical Alkyl and Vinyl Selenides
Damiano Tanini,* Simone Scarpelli, Elena Ermini and Antonella Capperucci
Dipartimento di Chimica ”Ugo Schiff”, Università di Firenze, Via della Lastruccia 3-13, 50019 Sesto Fiorentino, Italy.
Phone: +39 05545735-50/-52; Fax +39055 4574913; E-mail: damiano.tanini@unifi.it
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201#####
Abstract. Seleno-Michael additions of stable functionalised primary alkyl selenols to activated alkenes and alkynes
are described. In the presence of Al2O3, -hydroxy-, -amino-, and -mercapto selenols react smoothly with electron-
poor alkenes and alkynes to afford the corresponding unsymmetrical functionalised dialkyl- and alkyl-vinyl-selenides
in good yield. The very mild conditions allow a broad range of selenols and Michael acceptors to be converted into
the corresponding synthetically valuable seleno-Michael adducts, demonstrating high selectivity and excellent
functional group tolerance. Hydroxy- and mercapto-substituted vinyl selenides were efficiently employed for the
synthesis of functionalised 1,3-oxaselenolanes, 1,3-thiaselenolanes, and 1,4-thiaselenanes through intramolecular oxa-
and thia-Michael additions. Furthermore, a NaH-promoted lactonization enables the synthesis of variously substituted
2-oxo-1,4-oxaselenanes from hydroxy-vinyl-selenides. Evaluation of thiol peroxidase-like properties of novel
functionalised organoselenides demonstrated that they possess a remarkable catalytic antioxidant activity.
Keywords: Seleno-Michael; Selenols; Vinyl selenides; dialkyl selenides; antioxidants; Selenium
molecular complexity would be, therefore, particularly
interesting; enabling to explore new chemical space and
enlarge the existing catalysts and drugs libraries.
Introduction
Organoselenium compounds occupy a relevant position in
chemical sciences, with broad application in organic
synthesis,[1] materials science[2] and polymer chemistry.[3]
In addition, selenium-containing organic molecules play an
increasingly important role in biology and in medicinal
chemistry,[4] since they possess antioxidant,[5] enzyme
modulator,[6] anticancer,[7] and cells growth inhibitor[8]
activities. Due to their unique properties, in the last decade
organoselenides have attracted growing interest among
organic chemists, biologists, and medicinal chemists. In
this scenario, molecular complexity – measured by the
extent of bond saturation (fraction of sp3 hybridized
carbons, Fsp3) and the number of stereogenic centers – is of
paramount importance and represents one of the key
criteria in order to successfully develop new catalysts and
biologically active drug candidates.[9]
However, although several methods for the synthesis of
symmetrical dialkyl, diaryl, and divinyl selenides and
diselenides have been reported,[10,11] the synthesis of
polyfunctionalised unsymmetrical dialkyl and alkyl-vinyl
selenides remains a significant challenge. In addition,
owing to the use of harsh conditions, a number of synthetic
procedures are not tolerant of several functional groups,
thus further limiting the diversity of organoselenides
available. The development of a new, easy, general, and
versatile method to access differently functionalised and
substituted dialkyl and alkyl vinyl selenides with high
Among unsymmetrical organoselenides, an interesting
class is represented by -seleno carbonyl compounds,
which behave as enone -anion synthons.[12] The seleno-
Michael addition is a versatile tool to access synthetically
useful arylseleno carbonyl derivatives. Furthermore, the
seleno-Michael reaction is also important for the synthesis
of materials and bioactive molecules. For example, this
conjugate addition has been applied for the
functionalization of selenium containing dynamic
polymers.[13] The key step of the stereoselective synthesis
of 4’-selenonucleosides with antiviral activity is
represented by a seleno-Michael addition.[14] -Arylseleno
carbonyl compounds are commonly prepared by addition
of arylselenolates, often generated in situ upon treatment of
the corresponding diselenides with Zn/RuCl3,[15]
MeMgBr,[16] In-Me3SiCl,[17] or NaBH4,[18,19] to ,-
unsaturated carbonyl compounds. Alternative ways to
access -phenyseleno carbonyl compounds rely on the
reactivity of activated alkenes and alkynes with
PhSeZnCl[20] or with a phenylselenium borane, such as
PhSeBpin.[12,21] Additionally, a very limited number of
examples describe the use of benzeneselenol as a Michael
donor in conjugate additions to ,-unsaturated carbonyl
compounds.[22] Ceric ammonium nitrate (CAN),[23]
alkaloids,[24] and -cyclodextrins[25] are the most commonly
used catalysts or promoters.
1
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10.1002/adsc.201900168
Advanced Synthesis & Catalysis
Since Lewis acids are widely used for effecting Michael
addition reactions, we reasoned that a seleno-Michael
addition also could occur in the presence of a suitable
Lewis acid. Although the rather aggressive boron
trifluoride diethyl etherate and iron (III) chloride were not
effective (Table 1, entries 5-6) and led mainly to the
formation of the diselenide arising from the oxidation of 1a,
we were delighted to discover that -hydroxy selenol 1a
reacted with methyl acrylate in the presence of Al2O3 (1.0
eq.) in toluene at room temperature to yield the desired
hydroxy-substituted selenide 2a in 43% yield (Table 1,
entry 7). We found that higher reaction temperatures (entry
8) were detrimental to the reaction. Interestingly,
significant yields improvements were observed when
performing the reaction in the presence of an eccess of
Al2O3 at room temperature in toluene (entries 9, 10). In our
hands, the optimal reaction conditions proved to be the use
of 3.0 eq. of Al2O3 in toluene at ambient temperature (entry
10), enabling the selective formation of the desired selenide
2a in good yield, under very mild conditions. Further
excess of Al2O3 (4.0 eq.) and evaluation of other solvents
(entries 11 and 12) gave no yields improvement.
Furthermore, the on water reaction between hydroxy
selenol 1a and methyl acrylate was also tested.[20,25]
Interestingly, under these mild catalyst free conditions 2a
was formed, albeit in lower yields with respect to the use of
Al2O3/PhMe system (entries 13-14).
Having established optimal conditions for effective
seleno-Michael addition of alkyl selenols (Table 1, entry 8),
we proceeded to explore the scope of this methodology by
using a wide range of electron-deficient olefins and -
functionalised selenols, conveniently achieved through the
ring opening reaction of strained heterocycles with
(Me3Si)2Se.[27] Selenium-containing bis-ester 2b and
hydroxy substituted -keto-selenide 2c were efficiently
obtained through a clean conjugate addition of 1a to
dimethyl fumarate and methyl vinyl ketone, respectively
(Scheme 1). Interestingly, also sterically more demanding
Michael acceptors, such as 3-nonen-2-one and 2-
cyclohexen-1-one, proved to be reactive under these
conditions, allowing to access the functionalised -keto-
selenides 2d and 2e, albeit with a slight reduction in yield.
Furthermore, crotonaldehyde, acrylonitrile, and phenyl
vinyl sulfone could also be used in this conjugate addition
to yield the desired - seleno- aldehyde 2f, nitrile 2g, and
sulfone 2h, respectively (Scheme 1).
However, while the synthesis and the reactivity of -
arylseleno carbonyl compounds have been extensively
studied, to the best of our knowledge -alkylseleno
analogues have never been reported and the reactivity of
alkyl selenols with activated alkenes or alkynes remains
unexplored. Furthermore, thia-Michael additions of alkyl
thiols to electron-poor olefins have been widely studied and
applied in organic synthesis.[26] On the other hand, the
seleno-Michael reaction of functionalised alkyl selenols has
never been described, despite it would represent a powerful
tool for the formation of new C-Se bonds.
Recently, we reported a convenient procedure to
achieve stable -hydroxy-, -amino-, and -mercapto-
alkyl selenols through the ring opening of epoxides,
aziridines, and thiiranes with (Me3Si)2Se.[27] Such alkyl
selenols can be easily reacted with electrophiles, such as
alkyl halides, strained heterocycles, and acyl chlorides to
afford the corresponding functionalised selenides under
very mild conditions.[27] To further study the reactivity and
the chemical behaviour of alkyl selenols, we wished to
investigate whether novel unsymmetrical functionalised
dialkyl and alkyl vinyl selenides could be synthesized
through
a
conjugate addition, involving suitable
functionalised alkyl selenols and electron poor alkenes and
alkynes. In this communication, we report the synthesis and
the reactivity of novel functionalised unsymmetrical
dialkyl- and alkyl-vinyl-selenides, achieved through an
easy, versatile, and mild seleno-Michael addition of -
hydroxy-, -amino-, and -mercapto selenols to electron-
poor alkenes and alkynes.
Results and Discussion
We commenced our studies by establishing the conditions
required to promote the conjugate addition of the -
hydroxy selenol 1a[27] to methyl acrylate (Table 1). Several
reaction conditions and catalysts were investigated,
including organic or inorganic bases, Lewis acids, and on
water conditions. Although the tested inorganic bases were
unsuccessful in promoting this reaction (Table 1, entries 1-
2), the desired addition product could be achieved in rather
good yield by using
a slight excess of Et3N in
dichloromethane (entry 3). A comparable yield was
obtained when using a large eccess of amine (entry 4).
Having demonstrated that a variety of electron-deficient
alkenes could be employed in this seleno-Michael addition,
we therefore explored the scope of this reaction with
respect to differently substituted -hydroxy selenols. The
hydroxy substituted selenol 1b (R1 = n-Hexyl), bearing a
saturated alkyl chain could be employed in this procedure
(Scheme 1). The reaction of 1b with dimethyl fumarate and
3-nonen-2-one led to the formation of the functionalised
selenium containing bis-ester 2i and of the hydroxy -
ketoselenide 2j, having two linear alkyl substituents
(Scheme 1). 1,2-Hydroselenoalcohols bearing useful but
Table 1: Optimisation of the seleno-Michael addition of -
hydroxy selenol 1a to methyl acrylate.
labile
epichlorohydrin- derivatives 1c (R1 = CH2OBn) and 1d (R1
CH2Cl), were successfully converted into the
moieties,
such
as
benzylglycidol-
and
=
corresponding functionalised unsymmetrical selenides 2k,l
aYields referred to isolated product. bUse of 4.0 eq. of Al2O3 gave
comparable yield.
2
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10.1002/adsc.201900168
Advanced Synthesis & Catalysis
and 2m,n, by a selective conjugate addition to suitable
activated alkenes (Scheme 1).
This methodology was also applied to challenging -
mercaptoselenols 5a-b, where a competing thio-Michael
addition could occur. However, we were pleased to find
that, owing to the higher nucleophilicity of selenols with
respect to thiols, under the optimised Al2O3 mediated
conditions the selenol functionality proved to be much
more reactive than the thiol group. Therefore, variously
substituted mercapto-selenides, bearing ester (6a), keto
(6b,d), and cyano (6c) moieties were successfully obtained
from the corresponding -mercaptoselenols 5a and (R)-5b.
Although the formation of the product of double addition
could not be completely avoided (5-10% of the double
Michael adduct was formed), particularly noteworthy is the
possibility to achieve a good selectivity in the seleno-
Michael addition with respect to the competing thio-
Michael reaction. The presence of a free thiol functionality
offers the possibility to further functionalise selenides 6a-d.
To showcase that these class of molecules could be easily
functionalised, compound 7 was obtained in good yields by
treatment of mercapto-substituted -ketoselenide 6d with
In order to highlight the potential use of this mild
procedure, we applied it to the synthesis of the densely
functionalised selenide 2o, bearing the labile L-ascorbic
acid core and the chlorinated side chain. Treatment of
enantioenriched 1,2-hydroselenoalcohol (S)-1d with 6-O-
L-ascorbyl acrylate 2,3-dibenzyl ether gave 2o through a
clean seleno-Michael reaction.
To further enlarge the scope of this reaction we then
focused on -aminoselenols 3a-c.[27] A wide variety of
substituted enantioenriched
N-Tosyl and N-Boc
aminoselenides bearing ester (4a,b, 4f, 4i), keto (4c,d),
cyano (4e), and sulfone (4g) functionalities were smoothly
achieved from the corresponding 1,2-aminoselenols and
suitable electron-deficient alkenes. Interestingly, chiral N-
Tosyl amino-selenide 4h, containing four controlled
stereogenic centers, was efficiently obtained from 1,2-
hydroselenoamine 3b and the natural product-derived 2,3-
O-dibenzyl-5,6-O-L-ascorbyl diacrylate and (Scheme 1).
3
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10.1002/adsc.201900168
Advanced Synthesis & Catalysis
methyl acrylate in the presence of Et3N (Scheme 2). reacted smoothly with various activated alkynes, such as
Notably, this route allows to functionalise the SeH and the methyl
propiolate, 3-butyn-2-one, and diethyl
SH moieties – often characterized by a similar and acetylenedicarboxylate, to afford the corresponding seleno-
competitive reactivity – with two different Michael Michael products (8a-c). Hydroxy substituted alkyl-vinyl
acceptors.
selenides bearing ester (8a,b) and keto (8c) functionalities
were achieved in good yields and moderate
diastereoselectivity (see Scheme 3 and ESI for Z/E ratio).
Differently substituted -hydroxy selenols (1b-d),
including the labile epichlorohydrin derivative 1d,
performed well under these conditions, allowing to access a
variety of -hydroxy-alkyl-vinyl selenides bearing different
functionalities (8d-g).
Scheme 2: Double selective functionalization of -mercapto
selenols with different Michael acceptors.
Furthermore, also chiral N-Tosyl or N-Boc 1,2-
hydroselenoamines 3 and 1,2-mercaptoselenol 5b were
Having developed a selective and mild procedure[28] to
synthesise unsymmetrical dialkyl selenides exploiting the
reactivity of selenols with electron-deficient alkenes, we
wished to extend the scope to include activated alkynes.
This route would allow direct access to novel
unsymmetrical functionalised alkyl-vinyl selenides.
successfully
converted
into
the
corresponding
functionalised N-protected amino- and mercapto-
substituted alkyl-vinyl selenides 9a-c and 10a, upon
treatment with acetylenedicarboxylate and methyl
propiolate
(Scheme
3).
Moderate
to
good
Among organoselenium compounds, vinyl selenides are
arguably one of the most versatile and interesting classes
because of their wide use in stereoselective reactions.[29]
However, despite several methods have been developed for
their synthesis,[11] the use of transition metals and the harsh
conditions are the main drawbacks of the existing
methodologies. Therefore, we sought to develop a novel
mild procedure to achieve highly functionalised vinyl
selenides from alkyl selenols and activated alkynes. Results
of this investigation are reported in the Scheme 3.
diastereoselectivity was observed.
While the E/Z configuration of disubstituted
selenoalkenes 8a,c,f, 9b, and 10a could be easily assigned
3
by measuring the J(H,H), the determination of the alkene
geometry resulted more challenging for trisubstituted
derivatives 8b,d,e,g, 9a,c. For trisubstituted selenoalkenes
the configuration was assigned on the basis of vicinal H-
1
77Se coupling constants, 77Se NMR chemical shifts, and
nOe spectra (see ESI for details). The typical transoid
3J(H,Se) of Z isomers is larger than the cisoid 3J(H,Se) of E
isomers (Table S2 and Figure S3, ESI).[30] Furthermore,
quite huge differences were found about the 77Se NMR
chemical shift of Z and E diastereoisomers of vinyl
selenides. The 77Se NMR chemical shift of
Z
diastereoisomers resulted shifted downfield (up to 100
ppm) with respect to the resonance frequency of the 77Se
nucleus of E diastereoisomers. The presence of 1,5
intramolecular chalcogen bonding interactions (IChBs),[31]
involving the Se atom and the carbonyl oxygen, reasonably
accounts for the observed deshielding effect (Figure S2 and
S4, ESI).[32]
Intriguingly, hydroxy substituted ,-unsaturated -
selenoketones 8c,f proved to be rather unstable in slightly
acidic solvents, such as chloroform, where an
intramolecular oxa-Michael reaction led smoothly to the
formation of the corresponding ring closure products 11a,b
(Scheme 4). The progress of this mild cyclization reaction
1
could be easily monitored by H NMR spectroscopy, using
CDCl3 as the solvent (Figure 1). Nonetheless,
selenoketones 8c,f demonstrated a high stability in neutral
solvents (i.e. diethyl ether or toluene) where no formation
of the corresponding 1,3-oxaselenolanes was observed.
aReaction carried out using Et3N in CH2Cl2 gave the product in
53% yield and comparable d.r. bReaction carried out using Et3N in
CH2Cl2 gave the product in 58% yield and comparable d.r.
cReaction carried out using Et3N in CH2Cl2 gave the product in
62% yield and comparable d.r. dEt3N/CH2Cl2 conditions led to
poor seleno-Michael vs thia-Michael selectivity and a mixture of
products was formed. d.r. (Z/E ratio) was determined by 1H NMR.
Scheme 4: Synthesis of functionalised 1,3-oxaselenolanes 11a,b
from hydroxy-substituted alkyl-vinyl selenides 8c,f.
Scheme 3: Scope of seleno-Michael addition of substituted -
hydroxy-, -amino- and -mercapto-selenols to electron-deficient
alkynes.
Interestingly, the ,-unsaturated -selenoester 8a did
not undergo the expected intramolecular oxa-Michael
reaction under these conditions. Attempts to promote the
We were pleased to find that, under the above reported
Al2O3-promoted conditions, 1,2-hydroselenoalcohol 1a
4
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10.1002/adsc.201900168
Advanced Synthesis & Catalysis
ring closure reaction by using acids (Al2O3, BF3∙Et2O, HCl)
Prompted by these findings, to further demonstrate the
or bases (Et3N, KOH, NaH) were unsuccessful. The same versatility and the synthetic utility of functionalised alkyl
behaviour was observed for the amino substituted analogue vinyl selenides bearing two ester groups, we sought to
9b. Contrarily, owing to the strong nucleophile character of employ this class of organoselenium compounds for the
the mercapto moiety, ,-unsaturated -selenoester 10a construction of unsaturated selenium-containing -lactones.
provided access to disubstituted 1,3-thiaselenolane 12a, In
addition
to
their
occurrence
in
various
through a facile intramolecular thia-Michael reaction, pharmacologically relevant molecules,[33] chalcogen-
occurring in the presence of Et3N (Scheme 5, equation a).
containing six-membered heterocycles are useful in organic
synthesis34 and in medicinal chemistry.[14,35] Whilst
sulfurated derivatives have been widely investigated for
their properties, to the best of our knowledge, selenium-
containing analogues have received less attention.[36] The
paucity of such studies could be ascribed to the lack of
methodologies to access these molecules, thus we sought to
address this by developing new synthetic routes.
On the basis of our findings about the reactivity of
functionalised selenoalkenes, we envisaged hydroxy
substituted vinyl selenides as possible precursors of 1,4-
oxaselenane derivatives. Therefore, we evaluated whether
unsaturated selenium-containing -lactone 14a could be
accessed from hydroxy vinyl selenide (Z)-8b through a
base promoted intramolecular lactonization reaction.
Although Et3N and KOH were unsuccessful in promoting
the desired cyclisation, we found that (Z)-8b cyclised in the
presence of NaH in THF at low temperature, to yield the
desired unsaturated 2-oxo-1,4-oxaselenane 14a (Scheme 6).
Differently substituted and further functionalisable
derivatives 14b-c could be easily achieved under these
conditions from vinyl selenides (Z)-8d,e (Scheme 6).
Furthermore, the reaction temperature was found to be
crucial to isolate ,-unsaturated derivatives 14. Indeed,
when the reaction of (Z)-8b,g with NaH was allowed to
warm to room temperature, we observed exclusive
formation of 2-oxo-1,4-oxaselenanes 15a,b. It seems
reasonable that compounds 15 can be formed through the
oxa-Michael addition of EtO─, displaced in the NaH
promoted cyclisation of vinyl selenides 8, and ,-
unsaturated lactones 14.
Figure 1: 1H NMR (CDCl3) monitored intramolecular oxa-
Michael ring closure of hydroxy vinyl selenide 8e giving the 1,3-
oxaselenolane 11b. 1. Reaction time: 5 min (8e:11b = 90:10); 2.
Reaction time: 15 min (8e:11b = 65:35); 3. Reaction time: 30 min
(8e:11b = 48:52); 4. Reaction time: 60 min (8e:11b = 30:70); 5.
Reaction time: 90 min (8e:11b < 1:99).
Scheme 5: Synthesis of functionalised 1,3-thiaselenolanes 12a,b
and 1,4-thiaselenanes 13.
To further explore the versatility of these double hetero-
Michael reactions, we considered their application to the
synthesis of differently substituted sulfur- and selenium-
containing heterocycles of various ring sizes. We found
that the reaction of -mercaptoselenol (R)-5b with 3-butyn-
2-one, led straightforwardly to the disubstituted 1,3-
thiaselenolane 12b in good yield, through a one pot process
involving a seleno-Michael and a thia-Michael sequence
(Scheme 5, equation b). All attempts to isolate the plausible
intermediate 10b were unsuccessful, thus confirming the
aforementioned higher reactivity of ,-unsaturated -
selenoketones with respect to the corresponding
selenoesters. Similarly, the trisubstituted thiaselenane 13
was easily obtained in rather good yield from 5b and a
double activated Michael acceptor, such as the diethyl
acetylenedicarboxylate, exploiting the reactivity of the
diester intermediate 10c (Scheme 5, equation c).
Scheme 6: Synthesis of functionalised 2-oxo-1,4-oxaselenanes 14
and 15 from hydroxy substituted vinyl selenides
Having disclosed novel procedures for the synthesis of
unreported functionalized cyclic and open-chain selenides,
we next preliminary evaluated their catalytic antioxidant
activity as GPx mimics. Therefore, the thiol peroxidase-
like properties of selected compounds were determined by
using both the DTT oxidation text[5a,b,37,38] and the GSH/GR
coupled assay.[5a,37,38] Results of this investigation are
reported in Figures 2 and 3. All the tested compounds
exhibited remarkable GPx-like activity. Interestingly, -
seleno nitriles 2g,l and 2-oxo-1,4-oxaselenane 14a proved
to be the more active catalysts according to both tests. The
higher GPx-like activity of cyclic selenides with respect to
5
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10.1002/adsc.201900168
Advanced Synthesis & Catalysis
Conclusion
their acyclic analogues is in line with results of previous
reports.[37b] These findings are summarized in the Table 2
where T50 values, determined by DTT test and GSH/GR
coupled assay, are reported. Intriguingly, -hydroxy vinyl
selenide 8b displayed poor catalytic activity with respect to
similar saturated derivative. This behaviour might be
ascribed to the presence of 1,4 or 1,5 IChB interactions,
involving the selenium atom and one of the two carbonyl
groups.[5a]
In conclusion, the seleno-Michael addition of stable -
hydroxy-, -amino-, and -mercapto-selenols to electron
deficient alkenes and alkynes has been described, unveiling
a general, selective, and mild method for the synthesis of
novel variously functionalised dialkyl and alkyl-vinyl
selenides. The reaction scope was found to be broad, with
good functional-group tolerance demonstrated over a range
of selenols and electron-deficient alkenes and alkynes.
Notably, because of the very mild conditions, the
methodology enables the selective functionalization of the
selenol moiety in the presence of potentially competitive
hydroxy-, amino-, and especially mercapto groups.
Furthermore, vinyl selenides bearing hydroxy or the
mercapto moieties can be efficiently employed for the
synthesis of functionalised five- and six-membered
selenium-containing heterocycles. This study can provide
an important contribution to the methodologies for the
synthesis of densely functionalised acyclic and cyclic
organoselenides that, taking into account the growing
interest towards organoselenium compounds, will likely
find wide application for the synthesis of more complex
selenium-containing molecules. Furthermore, we found
that the nature of functional groups close to the selenium
atom strongly influences the catalytic antioxidant
properties of organoselenides, thus opening new
possibilities for the synthesis of antioxidants with enhanced
activity.
Figure 2: Oxidation of DTTred with H2O2 in the presence of Se-
containing catalysts (1 mol%). Reaction conditions: [DTTred]0 =
0.14 M, [H2O2]0 = 0.14 M, [catalyst] = 0.014 M, CD3OD (0.6
mL). In the control experiment the reaction was run with no
catalyst. The mean ± SD values of three separate experiments are
Experimental Section
General. All reactions were carried out in an oven-dried
glassware under inert atmosphere (N2). Solvents were dried
using a solvent purification system (Pure-Solv™). All
commercial materials were purchased from various
commercial sources and used as received, without further
purification. Flash column chromatography purifications
were performed with Silica gel 60 (230-400 mesh). Thin
layer chromatography was performed with TLC plates
Silica gel 60 F254, which was visualised under UV light, or
by staining with an ethanolic acid solution of p-
anisaldehyde followed by heating. High resolution mass
spectra (HRMS) were recorded by Electrospray Ionization
(ESI). GC-MS was performed on a Varian CP 3800/Saturn
2200 instrument.
reported.
Figure 3: NADPH-coupled GPx assay. Reaction conditions:
[NADPH]0 = 0.3 mM, [GSH]0 = 1.0 mM, [H2O2]0 = 2.5 mM,
[GR] = 4 units per mL, [catalyst] = 0.1 mM in pH 7.4 phosphate
buffer at ambient temperature. The mean ± SD values of three
separate experiments are reported.
1H and 13C NMR spectra were recorded in CDCl3 or
toluene-d8 using Mercury 400, Bruker 400 Ultrashield, and
Varian Gemini 200 spectrometers operating at 400 MHz
Table 2. Thiol-peroxidase like activity of functionalized
organoselenides according DTT and GSH/GR methods
1
and 200 MHz (for H), 100 MHz and 50 MHz (for 13C).
77Se NMR spectra were recorded using Bruker 400
Ultrashield and Varian Gemini 200 spectrometers,
operating at 76 MHz and 38 MHz, respectively. NMR
signals were referenced to nondeuterated residual solvent
signals (CDCl3: 7.26 ppm for 1H, 77.0 ppm for 13C;
1
Toluene-d8: 2.09 ppm for H, 20.4 ppm for 13C). Diphenyl
diselenide (PhSe)2 was used as an external reference for
77Se NMR (δ = 461 ppm). Chemical shifts () are given in
parts per million (ppm), and coupling constants (J) are
1
given in Hertz (Hz), rounded to the nearest 0.1 Hz. H
NMR data are reported as follows: chemical shift,
6
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10.1002/adsc.201900168
Advanced Synthesis & Catalysis
integration, multiplicity (s = singlet, d = doublet, t = triplet, GPx-like activity measurments. Glutathione peroxidase-
ap d = apparent doublet, m = multiplet, dd = doublet of like activity was evaluated following reported
doublet, bs = broad singlet, bd = broad doublet, ecc.), procedures.[5a,b, 37,38]
coupling constant (J) or line separation (ls), and assignment.
Where reported, NMR assignments are made according to
spin systems, using, where appropriate, 2D NMR
experiments (COSY, HSQC, HMBC) to assist the
assignment. -Hydroxy-, -amino-, and -mercapto-
selenols were synthesised from the corresponding epoxides,
aziridines, and thiiranes, following a reported procedure.[27]
2,3-O-Dibenzyl-6-O-L-ascorbyl acrylate and 2,3-O-
dibenzyl-5,6-O-L-ascorbyl diacrylate were prepared
according to reported procedures.[28]
Full experimental details, products characterization and
NMR spectra are reported in the Supplementary
Information.
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10.1002/adsc.201900168
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FULL PAPER
First seleno-Michael Reaction of Stable Functionalised
Alkyl Selenols: A new Tool for the Synthesis of Acyclic
and Cyclic Unsymmetrical Alkyl and Vinyl Selenides
Adv. Synth. Catal. Year, Volume, Page – Page
Damiano Tanini,* Simone Scarpelli, Elena Ermini,
Antonella Capperucci
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